rs80338876

Positions:

• chr7-100641198-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• 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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07274899).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFR2	NM_003227.4	c.64G>A	p.Val22Ile	missense_variant	2/18	ENST00000223051.8	NP_003218.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFR2	ENST00000223051.8	c.64G>A	p.Val22Ile	missense_variant	2/18	1	NM_003227.4	ENSP00000223051	P1

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

GnomAD3 exomes AF: 0.0000783 AC: 11 AN: 140518 Hom.: 0 AF XY: 0.000123 AC XY: 9 AN XY: 73462

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 SAS 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

Gnomad4 AFR exome AF: 0.000127

Gnomad4 AMR exome AF: 0.0000604

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000132

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000130

Gnomad4 OTH exome AF: 0.000122

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

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000201 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

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 02, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

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
MutationTaster	Benign	0.00013	A;A;A
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.20

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;