rs80338877

chr7-100641173-C-CG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003227.4(TFR2):c.88_89insC(p.Arg30ProfsTer31) variant causes a frameshift 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R30R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TFR2 NM_003227.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 1.20

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 83 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-100641173-C-CG is Pathogenic according to our data. Variant chr7-100641173-C-CG is described in ClinVar as [Pathogenic]. Clinvar id is 5381.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFR2	NM_003227.4	c.88_89insC	p.Arg30ProfsTer31	frameshift_variant	2/18	ENST00000223051.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFR2	ENST00000223051.8	c.88_89insC	p.Arg30ProfsTer31	frameshift_variant	2/18	1	NM_003227.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hemochromatosis type 3 Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2001	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Hereditary hemochromatosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 18, 2023

This sequence change creates a premature translational stop signal (p.Arg30Profs*31) in the TFR2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TFR2 are known to be pathogenic (PMID: 23600741, 26029709). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hemochromatosis (PMID: 11313241, 26408288). It has also been observed to segregate with disease in related individuals. This variant is also known as 84-88 insC (E60X). ClinVar contains an entry for this variant (Variation ID: 5381). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs80338877; hg19: chr7-100238796;