rs199695398

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BS1_Supporting

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency (the lower threshold of the 95% CI of 64/23748) of the c.1582G>A (p.Gly528Ser) variant in the MYO15A gene is 0.217% for African/African-American chromosomes by gnomAD, which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8423128/MONDO:0019497/005

Frequency

Genomes: 𝑓 0.00096 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

19

Clinical Significance

Likely benign reviewed by expert panel U:1B:5

Conservation

PhyloP100: 0.334
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 Likely_benign. Variant got -2 ACMG points.

BP4
For more information check the summary or visit ClinGen Evidence Repository.
BS1
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYO15ANM_016239.4 linkc.1582G>A p.Gly528Ser missense_variant Exon 2 of 66 ENST00000647165.2 NP_057323.3 Q9UKN7-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYO15AENST00000647165.2 linkc.1582G>A p.Gly528Ser missense_variant Exon 2 of 66 NM_016239.4 ENSP00000495481.1 Q9UKN7-1
MYO15AENST00000583079.1 linkn.1215G>A non_coding_transcript_exon_variant Exon 1 of 1 6

Frequencies

GnomAD3 genomes
AF:
0.000966
AC:
147
AN:
152218
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00323
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000589
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.000283
AC:
69
AN:
243688
Hom.:
0
AF XY:
0.000217
AC XY:
29
AN XY:
133478
show subpopulations
Gnomad AFR exome
AF:
0.00299
Gnomad AMR exome
AF:
0.000350
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000559
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000910
Gnomad OTH exome
AF:
0.000168
GnomAD4 exome
AF:
0.000103
AC:
151
AN:
1459018
Hom.:
1
Cov.:
36
AF XY:
0.0000978
AC XY:
71
AN XY:
725886
show subpopulations
Gnomad4 AFR exome
AF:
0.00311
Gnomad4 AMR exome
AF:
0.000358
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000151
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000108
Gnomad4 OTH exome
AF:
0.000199
GnomAD4 genome
AF:
0.000965
AC:
147
AN:
152336
Hom.:
1
Cov.:
33
AF XY:
0.00102
AC XY:
76
AN XY:
74486
show subpopulations
Gnomad4 AFR
AF:
0.00322
Gnomad4 AMR
AF:
0.000588
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000194
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000946
Alfa
AF:
0.000460
Hom.:
0
Bravo
AF:
0.000979
ESP6500AA
AF:
0.00279
AC:
11
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000249
AC:
30
EpiCase
AF:
0.00
EpiControl
AF:
0.0000594

ClinVar

Significance: Likely benign
Submissions summary: Uncertain:1Benign:5
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Benign:2
Oct 24, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 17, 2021
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1
Sep 27, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1582G>A (p.G528S) alteration is located in exon 2 (coding exon 1) of the MYO15A gene. This alteration results from a G to A substitution at nucleotide position 1582, causing the glycine (G) at amino acid position 528 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1
May 02, 2017
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

p.Gly528Ser in exon 2 of MYO15A: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, 3 mammals (naked mole-rat, chinchilla, and brush-tailed rat) have a serine (Ser) at this position despite high nearby amino acid sequence conservation. In addition, other computational tools do not suggest an impact to the protein. It has been identified in 0.3% (65/23654) of African chromosomes by the Genome Agg regation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199695398). -

MYO15A-related disorder Benign:1
Mar 02, 2020
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

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). -

Nonsyndromic genetic hearing loss Benign:1
Jul 22, 2021
ClinGen Hearing Loss Variant Curation Expert Panel
Significance: Likely benign
Review Status: reviewed by expert panel
Collection Method: curation

The filtering allele frequency (the lower threshold of the 95% CI of 64/23748) of the c.1582G>A (p.Gly528Ser) variant in the MYO15A gene is 0.217% for African/African-American chromosomes by gnomAD, which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP4. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.077
BayesDel_addAF
Benign
-0.61
T
BayesDel_noAF
Benign
-0.65
CADD
Benign
13
DANN
Benign
0.83
DEOGEN2
Benign
0.0086
T;T;T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.046
N
LIST_S2
Benign
0.44
T;.;T
M_CAP
Benign
0.021
T
MetaRNN
Benign
0.0038
T;T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
0.55
.;N;N
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-0.19
.;N;.
REVEL
Benign
0.017
Sift
Benign
0.62
.;T;.
Sift4G
Benign
0.49
T;T;.
Polyphen
0.0070
.;B;B
Vest4
0.12
MVP
0.15
ClinPred
0.00098
T
GERP RS
-2.1
Varity_R
0.043
gMVP
0.25

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: rs199695398; hg19: chr17-18023696; COSMIC: COSV99235066; API