rs41295899

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_003227.4(TFR2):c.1449C>T(p.Ser483Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,602,130 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0062 ( 9 hom., cov: 31)

Exomes 𝑓: 0.00059 ( 5 hom. )

Consequence

TFR2
NM_003227.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.334

Publications

1 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:

ENSG00000298392 (HGNC:):

ENSG00000298392 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 7-100628248-G-A is Benign according to our data. Variant chr7-100628248-G-A is described in ClinVar as Benign. ClinVar VariationId is 258986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.334 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00615 (900/146274) while in subpopulation AFR AF = 0.0208 (820/39462). AF 95% confidence interval is 0.0196. There are 9 homozygotes in GnomAd4. There are 430 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TFR2	NM_003227.4 link	c.1449C>T	p.Ser483Ser	synonymous_variant	Exon 11 of 18	ENST00000223051.8	NP_003218.2
TFR2	NM_001206855.3 link	c.936C>T	p.Ser312Ser	synonymous_variant	Exon 8 of 15		NP_001193784.1
LOC124901709	XR_007060454.1 link	n.434-2908G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFR2	ENST00000223051.8 link	c.1449C>T	p.Ser483Ser	synonymous_variant	Exon 11 of 18	1	NM_003227.4	ENSP00000223051.3

Frequencies

GnomAD3 genomes

AF:

0.00615

AC:

899

AN:

146182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0208

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00396

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00325

Gnomad NFE

AF:

0.0000894

Gnomad OTH

AF:

0.00845

GnomAD2 exomes

AF:

0.00147

AC:

369

AN:

251390

AF XY:

0.00102

show subpopulations

Gnomad AFR exome

AF:

0.0198

Gnomad AMR exome

AF:

0.000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000593

AC:

864

AN:

1455856

Hom.:

Cov.:

AF XY:

0.000507

AC XY:

367

AN XY:

724226

show subpopulations

African (AFR)

AF:

0.0209

AC:

696

AN:

33296

American (AMR)

AF:

0.00117

AC:

AN:

44518

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25904

East Asian (EAS)

AF:

0.00

AC:

AN:

39310

South Asian (SAS)

AF:

0.00

AC:

AN:

86200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52814

Middle Eastern (MID)

AF:

0.000699

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.0000307

AC:

AN:

1108112

Other (OTH)

AF:

0.00130

AC:

AN:

59978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

112

167

223

279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.00615

AC:

900

AN:

146274

Hom.:

Cov.:

AF XY:

0.00607

AC XY:

430

AN XY:

70866

show subpopulations

African (AFR)

AF:

0.0208

AC:

820

AN:

39462

American (AMR)

AF:

0.00395

AC:

AN:

14162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3434

East Asian (EAS)

AF:

0.00

AC:

AN:

4796

South Asian (SAS)

AF:

0.00

AC:

AN:

4546

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9556

Middle Eastern (MID)

AF:

0.00350

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0000894

AC:

AN:

67106

Other (OTH)

AF:

0.00837

AC:

AN:

2030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

127

169

211

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:

0.00296

Hom.:

Bravo

AF:

0.00644

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hemochromatosis type 3

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary hemochromatosis

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

1.3

(source)

DANN

Benign

0.86

PhyloP100

-0.33

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over