chr11-77202364-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_000260.4(MYO7A):c.5108C>T(p.Ala1703Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000261 in 1,565,632 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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. A1703E) has been classified as Uncertain significance.
Frequency
Consequence
NM_000260.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.5108C>T | p.Ala1703Val | missense_variant | Exon 37 of 49 | 1 | NM_000260.4 | ENSP00000386331.3 | ||
MYO7A | ENST00000458637.6 | c.4994C>T | p.Ala1665Val | missense_variant | Exon 37 of 49 | 1 | ENSP00000392185.2 | |||
MYO7A | ENST00000409619.6 | c.4961C>T | p.Ala1654Val | missense_variant | Exon 38 of 50 | 1 | ENSP00000386635.2 | |||
MYO7A | ENST00000458169.2 | c.2534C>T | p.Ala845Val | missense_variant | Exon 17 of 29 | 1 | ENSP00000417017.2 | |||
MYO7A | ENST00000670577.1 | n.2948C>T | non_coding_transcript_exon_variant | Exon 20 of 32 | ENSP00000499323.1 |
Frequencies
GnomAD3 genomes AF: 0.000329 AC: 50AN: 152064Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000259 AC: 45AN: 173552Hom.: 0 AF XY: 0.000270 AC XY: 25AN XY: 92478
GnomAD4 exome AF: 0.000253 AC: 358AN: 1413450Hom.: 1 Cov.: 30 AF XY: 0.000263 AC XY: 184AN XY: 698608
GnomAD4 genome AF: 0.000329 AC: 50AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25AN XY: 74398
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
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In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
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MYO7A-related disorder Benign:1Other:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Variant classified as Uncertain significance and reported on 08-21-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
not specified Uncertain:1
Variant classified as Uncertain Significance - Favor Benign. The p.Ala1703Val va riant in MYO7A has been previously reported by our laboratory in the heterozygou s state in 2 individuals with hearing loss, but a variant affecting the remainin g copy of the gene was not identified in either and an alternate etiology was fo und in one of them. It has been identified in 0.18% (16/8844) of Ashkenazi Jewis h chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadins titute.org/; dbSNP rs199561332) and is reported in ClinVar (variation ID: 43271) . Computational prediction tools and conservation analysis suggest that the p.Al a1703Val variant may not impact the protein, though this information is not pred ictive enough to rule out pathogenicity. In summary, while the clinical signific ance of the p.Ala1703Val variant is uncertain, these data suggest that it is mor e likely to be benign. ACMG/AMP Criteria applied: BP4. -
Autosomal dominant nonsyndromic hearing loss 11 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. -
Autosomal recessive nonsyndromic hearing loss 2 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. -
Usher syndrome type 1B Uncertain:1
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Usher syndrome type 1 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at