rs137853121
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001374504.1(TMPRSS6):c.1038C>A(p.Tyr346Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000051 in 1,567,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001374504.1 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMPRSS6 | NM_001374504.1 | c.1038C>A | p.Tyr346Ter | stop_gained | 9/18 | ENST00000676104.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMPRSS6 | ENST00000676104.1 | c.1038C>A | p.Tyr346Ter | stop_gained | 9/18 | NM_001374504.1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152198Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000560 AC: 1AN: 178518Hom.: 0 AF XY: 0.0000106 AC XY: 1AN XY: 94504
GnomAD4 exome AF: 0.00000424 AC: 6AN: 1414890Hom.: 0 Cov.: 34 AF XY: 0.00000572 AC XY: 4AN XY: 699108
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152316Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74474
ClinVar
Submissions by phenotype
Iron-refractory iron deficiency anemia Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2008 | - - |
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 02, 2023 | The heterozygous p.Tyr346Ter variant in TMPRSS6 was identified by our study, in the compound heterozygous state with a likely pathogenic variant (Variation ID: 1406), in one individual with iron-refractory iron deficiency anemia. This individual also carried a likely pathogenic variant (Variation ID: 1406), however the phase of these variants is unknown at this time. The p.Tyr346Ter variant in TMPRSS6 has been previously reported in one individual with iron-refractory iron deficiency anemia (PMID: 18408718) but has been identified in 0.009% (1/10706) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs137853121). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This previously reported individual was a compound heterozygote that carried a reported likely pathogenic variant in unknown phase (ClinVar Variation ID: 1406), which increases the likelihood that the p.Tyr346Ter variant is pathogenic.This variant has also been reported in ClinVar (Variation ID: 1405) and has been interpreted as pathogenic by OMIM and as likely pathogenic by GeneDx. This nonsense variant leads to a premature termination codon at position 346, which is predicted to lead to a truncated or absent protein. Loss of function of the TMPRSS6 gene is an established disease mechanism in autosomal recessive iron-refractory iron deficiency anemia. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive iron-refractory iron deficiency anemia. ACMG/AMP Criteria applied: PVS1, PM2_Supporting (Richards 2015). - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 26, 2022 | Observed with a second variant (phase unknown) in an individual with iron-refractory iron deficiency anemia in the literature (Finberg et al., 2008); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 25156943, 18408718) - |
TMPRSS6-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 30, 2023 | The TMPRSS6 c.1065C>A variant is predicted to result in premature protein termination (p.Tyr355*). This variant was reported along with a second likely disease-causing TMPRSS6 variant in an individual with iron-refractory iron deficiency anaemia (Finberg KE et al 2008. PubMed ID: 18408718). This variant is reported in 0.0093% of alleles in individuals of African descent in gnomAD. Nonsense variants in TMPRSS6 are expected to be pathogenic. This variant is interpreted as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at