rs200930743
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_016239.4(MYO15A):āc.7984C>Gā(p.Leu2662Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000654 in 1,613,588 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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_016239.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO15A | NM_016239.4 | c.7984C>G | p.Leu2662Val | missense_variant | 43/66 | ENST00000647165.2 | |
LOC105371567 | XR_001752809.1 | n.367+23G>C | intron_variant, non_coding_transcript_variant | ||||
MYO15A | XM_017024715.3 | c.7987C>G | p.Leu2663Val | missense_variant | 41/64 | ||
MYO15A | XM_017024714.3 | c.7924C>G | p.Leu2642Val | missense_variant | 40/63 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO15A | ENST00000647165.2 | c.7984C>G | p.Leu2662Val | missense_variant | 43/66 | NM_016239.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000532 AC: 81AN: 152240Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000583 AC: 145AN: 248654Hom.: 0 AF XY: 0.000503 AC XY: 68AN XY: 135214
GnomAD4 exome AF: 0.000667 AC: 974AN: 1461348Hom.: 2 Cov.: 30 AF XY: 0.000602 AC XY: 438AN XY: 726982
GnomAD4 genome ? AF: 0.000532 AC: 81AN: 152240Hom.: 0 Cov.: 32 AF XY: 0.000592 AC XY: 44AN XY: 74368
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MYO15A p.Leu2662Val variant was not identified in the literature but was identified in dbSNP (ID: rs200930743), ClinVar (classified as a VUS by EGL Genetic Diagnostics and Laboratory for Molecular Medicine) and LOVD 3.0 (classified as a VUS). The variant was identified in control databases in 164 of 280048 chromosomes (0 homozygous) at a frequency of 0.000586 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 131 of 128014 chromosomes (freq: 0.001023), European (Finnish) in 23 of 25032 chromosomes (freq: 0.000919), Other in 6 of 7134 chromosomes (freq: 0.000841) and African in 4 of 24074 chromosomes (freq: 0.000166), but was not observed in the Latino, Ashkenazi Jewish, East Asian or South Asian populations. The p.Leu2662 residue is conserved across mammals and other organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; 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. This variant is classified as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 21, 2014 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 05, 2019 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 19, 2024 | The c.7984C>G (p.L2662V) alteration is located in exon 43 (coding exon 42) of the MYO15A gene. This alteration results from a C to G substitution at nucleotide position 7984, causing the leucine (L) at amino acid position 2662 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Autosomal recessive nonsyndromic hearing loss 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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. - |
Hearing impairment Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Department of Otolaryngology ā Head & Neck Surgery, Cochlear Implant Center | Apr 12, 2021 | PM2_Supporting, BP4_Supporting - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at