rs119462987
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_001077365.2(POMT1):c.1939G>A(p.Ala647Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,972 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A647A) has been classified as Likely benign.
Frequency
Consequence
NM_001077365.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POMT1 | NM_001077365.2 | c.1939G>A | p.Ala647Thr | missense_variant | 19/20 | ENST00000402686.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POMT1 | ENST00000402686.8 | c.1939G>A | p.Ala647Thr | missense_variant | 19/20 | 1 | NM_001077365.2 | P1 | |
ENST00000415423.1 | n.62+8C>T | splice_region_variant, intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152150Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461822Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727218
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152150Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74328
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 19, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18513969, 17869517, 16717220, 22549409, 24491487, 17878207, 29419866, 31066050, 31589614, 31031587, 34602496, 30838351, 30454682, 33963534, 34565739, 19299310) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 13, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | POMT1: PM3:Strong, PM2 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 14, 2017 | - - |
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2012 | - - |
Walker-Warburg congenital muscular dystrophy;C1836373:Autosomal recessive limb-girdle muscular dystrophy type 2K;C5436962:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 669 of the POMT1 protein (p.Ala669Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ongenital muscular dystrophy and limb girdle muscular dystrophy (PMID: 16717220, 17869517, 17878207, 20816175; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3250). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POMT1 protein function. For these reasons, this variant has been classified as Pathogenic. - |
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 23, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at