NM_213599.3:c.1042G>A
Variant summary
Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM5PP3_Moderate
The NM_213599.3(ANO5):c.1042G>A(p.Gly348Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,613,874 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. G348C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_213599.3 missense
Scores
Clinical Significance
Conservation
Publications
- autosomal recessive limb-girdle muscular dystrophyInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- gnathodiaphyseal dysplasiaInheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
- autosomal recessive limb-girdle muscular dystrophy type 2LInheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
- Miyoshi muscular dystrophy 3Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152130Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000279 AC: 7AN: 251016 AF XY: 0.0000369 show subpopulations
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461744Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18AN XY: 727176 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152130Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74312 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:2
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Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L Pathogenic:1
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 348 of the ANO5 protein (p.Gly348Ser). This variant is present in population databases (rs139344099, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (internal data). ClinVar contains an entry for this variant (Variation ID: 281308). Invitae Evidence 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 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 ANO5 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Limb-girdle muscular dystrophy, recessive Uncertain:1
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ANO5-Related Muscle Diseases Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Miyoshi myopathy Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at