chr7-100641173-C-CG
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_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
NM_003227.4 frameshift
Scores
Not classified
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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 90 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
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hemochromatosis type 3 Pathogenic:1Other: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
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Prediction
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at