rs763919775

Positions:

• chr7-100633290-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003227.4(TFR2):​c.665A>T​(p.Glu222Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: TFR2 NM_003227.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 3.34

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFR2	NM_003227.4	c.665A>T	p.Glu222Val	missense_variant	5/18	ENST00000223051.8	NP_003218.2
TFR2	NM_001206855.3	c.152A>T	p.Glu51Val	missense_variant	2/15		NP_001193784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFR2	ENST00000223051.8	c.665A>T	p.Glu222Val	missense_variant	5/18	1	NM_003227.4	ENSP00000223051.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 246834 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134248

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000903

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hemochromatosis type 3 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 28, 2020

- -

Hereditary hemochromatosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 14, 2021

This sequence change replaces glutamic acid with valine at codon 222 of the TFR2 protein (p.Glu222Val). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and valine. This variant has not been reported in the literature in individuals affected with TFR2-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.;T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.0046
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.77	T;T;.
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;.;M
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.12	T;T;T
Sift4G	Uncertain	0.030	D;D;D
Polyphen		0.81	P;.;P
Vest4		0.57
MutPred		0.46		Loss of disorder (P = 0.004);Loss of disorder (P = 0.004);Loss of disorder (P = 0.004);
MVP		0.53
MPC		0.83
ClinPred		0.90	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.84

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: rs763919775; hg19: chr7-100230913;