rs41303501

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003227.4(TFR2):c.1364G>A(p.Arg455Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,614,034 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0031 ( 5 hom. )

Consequence

TFR2
NM_003227.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4O:2

Conservation

PhyloP100: 2.53

Publications

25 publications found

Variant links:

Genes affected

TFR2 (HGNC:11762): (transferrin receptor 2) This gene encodes a single-pass type II membrane protein, which is a member of the transferrin receptor-like family. This protein mediates cellular uptake of transferrin-bound iron, and may be involved in iron metabolism, hepatocyte function and erythrocyte differentiation. Mutations in this gene have been associated with hereditary hemochromatosis type III. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, May 2011]

TFR2 Gene-Disease associations (from GenCC):

hemochromatosis type 3
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P

TFR2 links:

LOC124901709 (HGNC:):

LOC124901709 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02515769).

BP6

Variant 7-100629279-C-T is Benign according to our data. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383. Variant chr7-100629279-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 5383.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00209 (318/152328) while in subpopulation NFE AF = 0.00344 (234/68028). AF 95% confidence interval is 0.00308. There are 0 homozygotes in GnomAd4. There are 145 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFR2	NM_003227.4 link	c.1364G>A	p.Arg455Gln	missense_variant	Exon 10 of 18	ENST00000223051.8	NP_003218.2	Q9UP52-1
TFR2	NM_001206855.3 link	c.851G>A	p.Arg284Gln	missense_variant	Exon 7 of 15		NP_001193784.1	Q9UP52-2
LOC124901709	XR_007060454.1 link	n.434-1877C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFR2	ENST00000223051.8 link	c.1364G>A	p.Arg455Gln	missense_variant	Exon 10 of 18	1	NM_003227.4	ENSP00000223051.3		Q9UP52-1

Frequencies

GnomAD3 genomes

AF:

0.00209

AC:

318

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00358

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00344

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00194

AC:

489

AN:

251440

AF XY:

0.00194

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00337

Gnomad NFE exome

AF:

0.00325

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00310

AC:

4538

AN:

1461706

Hom.:

Cov.:

AF XY:

0.00303

AC XY:

2203

AN XY:

727152

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33480

American (AMR)

AF:

0.000358

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.000522

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00384

AC:

205

AN:

53398

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00371

AC:

4122

AN:

1111886

Other (OTH)

AF:

0.00212

AC:

128

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

306

611

917

1222

1528

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

312

468

624

780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00209

AC:

318

AN:

152328

Hom.:

Cov.:

AF XY:

0.00195

AC XY:

145

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.000746

AC:

AN:

41574

American (AMR)

AF:

0.000589

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000828

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00358

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00344

AC:

234

AN:

68028

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00277

Hom.:

Bravo

AF:

0.00160

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00203

AC:

247

EpiCase

AF:

0.00278

EpiControl

AF:

0.00332

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hemochromatosis type 3

Uncertain:1Benign:1Other:1

Apr 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hereditary hemochromatosis

Benign:1

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TFR2: BP4, BS2 -

TFR2-related disorder

Benign:1

Oct 09, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hemochromatosis, type 1, modifier of

Other:1

Aug 01, 2002

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;T

Eigen

Benign

-0.032

Eigen_PC

Benign

-0.072

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.81

T;.

M_CAP

Benign

0.016

MetaRNN

Benign

0.025

T;T

MetaSVM

Benign

-0.77

MutationAssessor

Uncertain

2.2

M;M

PhyloP100

2.5

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.16

Sift

Benign

0.33

T;T

Sift4G

Benign

0.15

T;T

Polyphen

0.84

P;P

Vest4

0.49

MVP

0.64

MPC

0.55

ClinPred

0.017

GERP RS

3.5

Varity_R

0.23

gMVP

0.82

Mutation Taster

=298/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over