chr7-100631032-G-T

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.1127C>A(p.Ala376Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0047 in 1,592,294 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0037 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0048 ( 20 hom. )

Consequence

TFR2
NM_003227.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 2.54

Publications

9 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: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, PanelApp Australia

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=0.00885278).

BP6

Variant 7-100631032-G-T is Benign according to our data. Variant chr7-100631032-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 461196.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0037 (563/152326) while in subpopulation NFE AF = 0.00472 (321/68016). AF 95% confidence interval is 0.00429. There are 9 homozygotes in GnomAd4. There are 256 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003227.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFR2	NM_003227.4	MANE Select	c.1127C>A	p.Ala376Asp	missense	Exon 9 of 18	NP_003218.2
	TFR2	NM_001206855.3		c.614C>A	p.Ala205Asp	missense	Exon 6 of 15	NP_001193784.1	Q9UP52-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TFR2	ENST00000223051.8	TSL:1 MANE Select	c.1127C>A	p.Ala376Asp	missense	Exon 9 of 18	ENSP00000223051.3	Q9UP52-1
TFR2	ENST00000855275.1		c.1223C>A	p.Ala408Asp	missense	Exon 11 of 20	ENSP00000525334.1
TFR2	ENST00000855257.1		c.1127C>A	p.Ala376Asp	missense	Exon 10 of 20	ENSP00000525316.1

Frequencies

GnomAD3 genomes

AF:

0.00370

AC:

563

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000941

Gnomad AMI

AF:

0.129

Gnomad AMR

AF:

0.00426

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00472

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00269

AC:

596

AN:

221158

AF XY:

0.00272

show subpopulations

Gnomad AFR exome

AF:

0.000504

Gnomad AMR exome

AF:

0.00257

Gnomad ASJ exome

AF:

0.000120

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00156

Gnomad NFE exome

AF:

0.00416

Gnomad OTH exome

AF:

0.00357

GnomAD4 exome

AF:

0.00480

AC:

6917

AN:

1439968

Hom.:

Cov.:

AF XY:

0.00466

AC XY:

3339

AN XY:

715966

show subpopulations

African (AFR)

AF:

0.000713

AC:

AN:

32252

American (AMR)

AF:

0.00229

AC:

AN:

39322

Ashkenazi Jewish (ASJ)

AF:

0.0000808

AC:

AN:

24760

East Asian (EAS)

AF:

0.00

AC:

AN:

39492

South Asian (SAS)

AF:

0.00149

AC:

125

AN:

83750

European-Finnish (FIN)

AF:

0.00172

AC:

AN:

52338

Middle Eastern (MID)

AF:

0.000404

AC:

AN:

4948

European-Non Finnish (NFE)

AF:

0.00575

AC:

6347

AN:

1103830

Other (OTH)

AF:

0.00402

AC:

238

AN:

59276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

353

706

1060

1413

1766

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

246

492

738

984

1230

<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:

0.00370

AC:

563

AN:

152326

Hom.:

Cov.:

AF XY:

0.00344

AC XY:

256

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000938

AC:

AN:

41580

American (AMR)

AF:

0.00425

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00124

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000941

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00472

AC:

321

AN:

68016

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

122

153

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00400

Hom.:

Bravo

AF:

0.00396

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.000911

AC:

ESP6500EA

AF:

0.00420

AC:

ExAC

AF:

0.00255

AC:

309

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Hemochromatosis type 3 (2)

Hereditary hemochromatosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.47

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.71

M_CAP

Benign

0.022

MetaRNN

Benign

0.0089

MetaSVM

Benign

-0.71

MutationAssessor

Pathogenic

3.8

PhyloP100

2.5

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.20

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0070

Polyphen

0.92

Vest4

0.50

MVP

0.74

MPC

0.91

ClinPred

0.072

GERP RS

3.7

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.37

gMVP

0.84

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over