NM_016239.4:c.8322C>T

Variant names:

• chr17-18155207-C-T
• rs712272
• NM_016239.4:c.8322C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_016239.4(MYO15A):​c.8322C>T​(p.Ser2774Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.384 in 1,613,392 control chromosomes in the GnomAD database, including 124,843 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9414 hom., cov: 33)
  • Exomes 𝑓: 0.39 (115429 hom.)
• Consequence: MYO15A NM_016239.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.06

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]

LOC105371567 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 17-18155207-C-T is Benign according to our data. Variant chr17-18155207-C-T is described in ClinVar as [Benign]. Clinvar id is 45767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18155207-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.06 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.8322C>T	p.Ser2774Ser	synonymous_variant	Exon 46 of 66	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.8322C>T	p.Ser2774Ser	synonymous_variant	Exon 46 of 66		NM_016239.4	ENSP00000495481.1

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51246 AN: 152010 Hom.: 9414 Cov.: 33

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.299

Gnomad ASJ AF: 0.395

Gnomad EAS AF: 0.0807

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.422

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.417

Gnomad OTH AF: 0.329

GnomAD3 exomes AF: 0.335 AC: 83264 AN: 248478 Hom.: 15321 AF XY: 0.335 AC XY: 45131 AN XY: 134908

Gnomad AFR exome AF: 0.228

Gnomad AMR exome AF: 0.279

Gnomad ASJ exome AF: 0.408

Gnomad EAS exome AF: 0.0872

Gnomad SAS exome AF: 0.215

Gnomad FIN exome AF: 0.437

Gnomad NFE exome AF: 0.411

Gnomad OTH exome AF: 0.366

GnomAD4 exome AF: 0.389 AC: 567824 AN: 1461264 Hom.: 115429 Cov.: 52 AF XY: 0.383 AC XY: 278613 AN XY: 726936

Gnomad4 AFR exome AF: 0.233

Gnomad4 AMR exome AF: 0.282

Gnomad4 ASJ exome AF: 0.400

Gnomad4 EAS exome AF: 0.0981

Gnomad4 SAS exome AF: 0.215

Gnomad4 FIN exome AF: 0.437

Gnomad4 NFE exome AF: 0.421

Gnomad4 OTH exome AF: 0.363

GnomAD4 genome AF: 0.337 AC: 51264 AN: 152128 Hom.: 9414 Cov.: 33 AF XY: 0.331 AC XY: 24607 AN XY: 74362

Gnomad4 AFR AF: 0.238

Gnomad4 AMR AF: 0.299

Gnomad4 ASJ AF: 0.395

Gnomad4 EAS AF: 0.0812

Gnomad4 SAS AF: 0.212

Gnomad4 FIN AF: 0.422

Gnomad4 NFE AF: 0.417

Gnomad4 OTH AF: 0.326

Alfa AF: 0.388 Hom.: 8947

Bravo AF: 0.322

Asia WGS AF: 0.163 AC: 569 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ser2774Ser in Exon 46 of MYO15A: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 40.1% (2748/6852) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs712272). -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 09, 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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 3 Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	6.6
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs712272; hg19: chr17-18058521; COSMIC: COSV52754131; COSMIC: COSV52754131;