rs56132571
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_001382347.1(MYO5A):c.3136G>A(p.Val1046Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,613,794 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001382347.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO5A | NM_001382347.1 | c.3136G>A | p.Val1046Met | missense_variant | 23/42 | ENST00000399233.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO5A | ENST00000399233.7 | c.3136G>A | p.Val1046Met | missense_variant | 23/42 | 5 | NM_001382347.1 |
Frequencies
GnomAD3 genomes ? AF: 0.000972 AC: 148AN: 152208Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00103 AC: 256AN: 249458Hom.: 0 AF XY: 0.00120 AC XY: 162AN XY: 135344
GnomAD4 exome AF: 0.00161 AC: 2358AN: 1461468Hom.: 2 Cov.: 31 AF XY: 0.00161 AC XY: 1172AN XY: 727036
GnomAD4 genome ? AF: 0.000972 AC: 148AN: 152326Hom.: 0 Cov.: 32 AF XY: 0.00102 AC XY: 76AN XY: 74494
ClinVar
Submissions by phenotype
not provided Benign:4
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 09, 2018 | See Variant Classification Assertion Criteria. - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | MYO5A: BP4, BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 10, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MYO5A p.Val1046Met variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs56132571), ClinVar (classified as a VUS by the University of Chicago and Praxis fuer Humangenetik Tuebingen) and LOVD 3.0. The variant was identified in control databases in 280 of 280870 chromosomes at a frequency of 0.000997 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 212 of 128674 chromosomes (freq: 0.001648), South Asian in 43 of 30596 chromosomes (freq: 0.001405), Other in 6 of 7142 chromosomes (freq: 0.00084), Latino in 13 of 35340 chromosomes (freq: 0.000368), European (Finnish) in 3 of 25030 chromosomes (freq: 0.00012), African in 2 of 24204 chromosomes (freq: 0.000083) and East Asian in 1 of 19524 chromosomes (freq: 0.000051), while the variant was not observed in the Ashkenazi Jewish population. The p.Val1046 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 12, 2015 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 13, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Griscelli syndrome type 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Dec 10, 2020 | - - |
Intellectual disability Benign:1
Likely benign, no assertion criteria provided | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | Jan 01, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at