17-18121038-G-T

Variant names:

• chr17-18121038-G-T
• rs79760961
• NM_016239.4:c.2238G>T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4 BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency (the lower threshold of the 95% CI of 511/11092) of the p.Arg746Ser variant in the MYO15A gene is 4.27% for African chromosomes (including 8 homozygous observations) by gnomAD, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). 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 benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BA1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8423237/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.015 (44 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (41 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Benign reviewed by expert panel B:7
• Conservation: PhyloP100: 0.105

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.2238G>T	p.Arg746Ser	missense_variant	Exon 2 of 66	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.2238G>T	p.Arg746Ser	missense_variant	Exon 2 of 66		NM_016239.4	ENSP00000495481.1
MYO15A	ENST00000583079.1	n.1871G>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2201 AN: 151052 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.0483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000192

Gnomad OTH AF: 0.0126

GnomAD3 exomes AF: 0.00195 AC: 213 AN: 109144 Hom.: 6 AF XY: 0.00153 AC XY: 93 AN XY: 60676

Gnomad AFR exome AF: 0.0488

Gnomad AMR exome AF: 0.00284

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000503

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.00365

GnomAD4 exome AF: 0.00139 AC: 1884 AN: 1358612 Hom.: 41 Cov.: 36 AF XY: 0.00125 AC XY: 839 AN XY: 670106

Gnomad4 AFR exome AF: 0.0450

Gnomad4 AMR exome AF: 0.00399

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000913

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000214

Gnomad4 OTH exome AF: 0.00382

GnomAD4 genome AF: 0.0146 AC: 2207 AN: 151160 Hom.: 44 Cov.: 32 AF XY: 0.0140 AC XY: 1037 AN XY: 73878

Gnomad4 AFR AF: 0.0483

Gnomad4 AMR AF: 0.0106

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000192

Gnomad4 OTH AF: 0.0125

Alfa AF: 0.00624 Hom.: 2

Bravo AF: 0.0169

ESP6500AA AF: 0.0259 AC: 51

ESP6500EA AF: 0.000403 AC: 2

ExAC AF: 0.00126 AC: 60

Asia WGS AF: 0.00272 AC: 9 AN: 3324

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arg746Ser in Exon 02 of MYO15A: This variant is not expected to have clinical si gnificance because it has been identified in 2.6% (42/1612) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs79760961). -

Dec 18, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jul 08, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nonsyndromic genetic hearing loss Benign:1

Jun 15, 2021

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The filtering allele frequency (the lower threshold of the 95% CI of 511/11092) of the p.Arg746Ser variant in the MYO15A gene is 4.27% for African chromosomes (including 8 homozygous observations) by gnomAD, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). 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 benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BA1, BP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	9.8
DANN	Benign	0.85
DEOGEN2	Benign	0.019	T;T;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.46	T;.;T
MetaRNN	Benign	0.0025	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.69	.;N;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.75	.;N;.
REVEL	Benign	0.12
Sift	Uncertain	0.0080	.;D;.
Sift4G	Benign	0.081	T;T;.
Polyphen		0.29	.;B;B
Vest4		0.32
MutPred		0.36		Gain of glycosylation at R746 (P = 0.0109);Gain of glycosylation at R746 (P = 0.0109);Gain of glycosylation at R746 (P = 0.0109);
MVP		0.54
ClinPred		0.0097	T
GERP RS		1.1
Varity_R		0.097
gMVP		0.34

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

Other links and lift over

dbSNP: rs79760961; hg19: chr17-18024352;