rs541803470
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_001164507.2(NEB):c.4337G>T(p.Gly1446Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,608 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1446D) has been classified as Likely benign.
Frequency
Consequence
NM_001164507.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.4337G>T | p.Gly1446Val | missense_variant | 38/182 | ENST00000427231.7 | |
NEB | NM_001164508.2 | c.4337G>T | p.Gly1446Val | missense_variant | 38/182 | ENST00000397345.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.4337G>T | p.Gly1446Val | missense_variant | 38/182 | 5 | NM_001164508.2 | P5 | |
NEB | ENST00000427231.7 | c.4337G>T | p.Gly1446Val | missense_variant | 38/182 | 5 | NM_001164507.2 | A2 | |
NEB | ENST00000409198.5 | c.4337G>T | p.Gly1446Val | missense_variant | 38/150 | 5 | |||
NEB | ENST00000484968.1 | n.189G>T | non_coding_transcript_exon_variant | 1/3 | 4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461608Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10AN XY: 727102
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Nemaline myopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 16, 2023 | Variant summary: NEB c.4337G>T (p.Gly1446Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249100 control chromosomes (gnomAD). c.4337G>T has been reported in the literature as a compound heterozygous genotype with other deleterious variants in at least three unique individuals affected with Nemaline Myopathy 2 (e.g., Lehtokari_2014, Hindocha_2017). At least one of these individuals was comprehensively phenotyped with features of congenital nemaline myopathy co-presenting with systemic lupus erythematosus (Hindocha_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28977494, 25205138). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Nemaline myopathy 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 14, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at