rs186426892

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_016239.4(MYO15A):​c.4719G>A​(p.Ala1573Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,613,642 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0019 ( 10 hom. )

Consequence

MYO15A
NM_016239.4 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.892
Variant links:
Genes affected
MYO15A (HGNC:7594): (myosin XVA) This gene encodes an unconventional myosin. This protein differs from other myosins in that it has a long N-terminal extension preceding the conserved motor domain. Studies in mice suggest that this protein is necessary for actin organization in the hair cells of the cochlea. Mutations in this gene have been associated with profound, congenital, neurosensory, nonsyndromal deafness. This gene is located within the Smith-Magenis syndrome region on chromosome 17. Read-through transcripts containing an upstream gene and this gene have been identified, but they are not thought to encode a fusion protein. Several alternatively spliced transcript variants have been described, but their full length sequences have not been determined. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
Variant 17-18136626-G-A is Benign according to our data. Variant chr17-18136626-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178441.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=2}. Variant chr17-18136626-G-A is described in Lovd as [Likely_benign].
BS2
High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYO15ANM_016239.4 linkuse as main transcriptc.4719G>A p.Ala1573Ala synonymous_variant 15/66 ENST00000647165.2 NP_057323.3 Q9UKN7-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYO15AENST00000647165.2 linkuse as main transcriptc.4719G>A p.Ala1573Ala synonymous_variant 15/66 NM_016239.4 ENSP00000495481.1 Q9UKN7-1

Frequencies

GnomAD3 genomes
AF:
0.00137
AC:
209
AN:
152204
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000555
Gnomad AMI
AF:
0.0175
Gnomad AMR
AF:
0.00183
Gnomad ASJ
AF:
0.000865
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.000828
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00182
Gnomad OTH
AF:
0.00478
GnomAD3 exomes
AF:
0.00146
AC:
362
AN:
248576
Hom.:
1
AF XY:
0.00156
AC XY:
211
AN XY:
134974
show subpopulations
Gnomad AFR exome
AF:
0.000323
Gnomad AMR exome
AF:
0.00142
Gnomad ASJ exome
AF:
0.000994
Gnomad EAS exome
AF:
0.0000556
Gnomad SAS exome
AF:
0.00124
Gnomad FIN exome
AF:
0.0000948
Gnomad NFE exome
AF:
0.00214
Gnomad OTH exome
AF:
0.00248
GnomAD4 exome
AF:
0.00186
AC:
2721
AN:
1461320
Hom.:
10
Cov.:
32
AF XY:
0.00192
AC XY:
1397
AN XY:
726966
show subpopulations
Gnomad4 AFR exome
AF:
0.000807
Gnomad4 AMR exome
AF:
0.00152
Gnomad4 ASJ exome
AF:
0.00103
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00117
Gnomad4 FIN exome
AF:
0.0000756
Gnomad4 NFE exome
AF:
0.00206
Gnomad4 OTH exome
AF:
0.00260
GnomAD4 genome
AF:
0.00138
AC:
210
AN:
152322
Hom.:
1
Cov.:
33
AF XY:
0.00122
AC XY:
91
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.000577
Gnomad4 AMR
AF:
0.00183
Gnomad4 ASJ
AF:
0.000865
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000829
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00182
Gnomad4 OTH
AF:
0.00473
Alfa
AF:
0.00131
Hom.:
0
Bravo
AF:
0.00173
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.00229
EpiControl
AF:
0.00326

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitterclinical testingGeneDxJul 11, 2019- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2023MYO15A: BP4, BP7 -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024- -
not specified Benign:2
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 31, 2016p.Ala1573Ala in exon 15 of MYO15A: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wi thin the splice consensus sequence, and has been identified in 0.2% (134/64560) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs186426892). -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsAug 24, 2020- -
Autosomal recessive nonsyndromic hearing loss 3 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.83
CADD
Benign
0.073
DANN
Benign
0.50

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs186426892; hg19: chr17-18039940; COSMIC: COSV99231381; COSMIC: COSV99231381; API