7-100641198-C-T

Variant names:

• chr7-100641198-C-T
• rs80338876
• NM_003227.4:c.64G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_003227.4(TFR2):​c.64G>A​(p.Val22Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,532,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. V22V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: TFR2 NM_003227.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 0.717

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07274899).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFR2	NM_003227.4	c.64G>A	p.Val22Ile	missense_variant	Exon 2 of 18	ENST00000223051.8	NP_003218.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFR2	ENST00000223051.8	c.64G>A	p.Val22Ile	missense_variant	Exon 2 of 18	1	NM_003227.4	ENSP00000223051.3

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152048 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000783 AC: 11 AN: 140518 AF XY: 0.000123

Gnomad AFR exome AF: 0.000119

Gnomad AMR exome AF: 0.0000448

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000166

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000111 AC: 153 AN: 1380384 Hom.: 0 Cov.: 31 AF XY: 0.000124 AC XY: 84 AN XY: 678454

African (AFR) AF: 0.000127 AC: 4 AN: 31404

American (AMR) AF: 0.0000604 AC: 2 AN: 33086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23588

East Asian (EAS) AF: 0.00 AC: 0 AN: 36060

South Asian (SAS) AF: 0.0000132 AC: 1 AN: 76018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5560

European-Non Finnish (NFE) AF: 0.000130 AC: 139 AN: 1069106

Other (OTH) AF: 0.000122 AC: 7 AN: 57312

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152166 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9 AN XY: 74376

African (AFR) AF: 0.0000723 AC: 3 AN: 41502

American (AMR) AF: 0.000262 AC: 4 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.000192 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.0000617 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hemochromatosis type 3 Uncertain:2 Other:1

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. -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 02, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	13
DANN	Benign	0.86
DEOGEN2	Benign	0.051	T;.;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.58	T;T;.
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.073	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.34	N;.;N
PhyloP100		0.72
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.24	N;N;N
REVEL	Uncertain	0.29
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0010	B;.;B
Vest4		0.64
MVP		0.50
MPC		0.27
ClinPred		0.0096	T
GERP RS		3.3
PromoterAI		-0.038	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.20
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs80338876; hg19: chr7-100238821; COSMIC: COSV50513962; COSMIC: COSV50513962;