rs854772

Variant names:

• chr17-18151915-G-A
• rs854772
• NM_016239.4:c.7857G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016239.4(MYO15A):​c.7857G>A​(p.Gly2619Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 1,569,040 control chromosomes in the GnomAD database, including 273,422 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23974 hom., cov: 32)
  • Exomes 𝑓: 0.58 (249448 hom.)
• Consequence: MYO15A NM_016239.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.101
• Publications: 25 publications found

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]

MYO15A Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC124903944 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 17-18151915-G-A is Benign according to our data. Variant chr17-18151915-G-A is described in ClinVar as Benign. ClinVar VariationId is 45761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.101 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.621 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.7857G>A	p.Gly2619Gly	synonymous_variant	Exon 41 of 66	ENST00000647165.2	NP_057323.3
MYO15A	XM_017024715.3	c.7860G>A	p.Gly2620Gly	synonymous_variant	Exon 39 of 64		XP_016880204.1
MYO15A	XM_017024714.3	c.7797G>A	p.Gly2599Gly	synonymous_variant	Exon 38 of 63		XP_016880203.1
LOC124903944	XR_007065652.1	n.74-9C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.7857G>A	p.Gly2619Gly	synonymous_variant	Exon 41 of 66		NM_016239.4	ENSP00000495481.1

Frequencies

GnomAD3 genomes AF: 0.549 AC: 83400 AN: 151952 Hom.: 23939 Cov.: 32

Gnomad AFR AF: 0.507

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.477

Gnomad ASJ AF: 0.675

Gnomad EAS AF: 0.0902

Gnomad SAS AF: 0.389

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.626

Gnomad OTH AF: 0.565

GnomAD2 exomes AF: 0.510 AC: 91292 AN: 179054 AF XY: 0.511

Gnomad AFR exome AF: 0.500

Gnomad AMR exome AF: 0.397

Gnomad ASJ exome AF: 0.682

Gnomad EAS exome AF: 0.0916

Gnomad FIN exome AF: 0.582

Gnomad NFE exome AF: 0.620

Gnomad OTH exome AF: 0.571

GnomAD4 exome AF: 0.584 AC: 827406 AN: 1416970 Hom.: 249448 Cov.: 57 AF XY: 0.579 AC XY: 405639 AN XY: 700210

African (AFR) AF: 0.512 AC: 16834 AN: 32886

American (AMR) AF: 0.410 AC: 15165 AN: 36964

Ashkenazi Jewish (ASJ) AF: 0.678 AC: 17135 AN: 25256

East Asian (EAS) AF: 0.101 AC: 3853 AN: 38122

South Asian (SAS) AF: 0.407 AC: 32722 AN: 80414

European-Finnish (FIN) AF: 0.582 AC: 29252 AN: 50298

Middle Eastern (MID) AF: 0.647 AC: 3693 AN: 5710

European-Non Finnish (NFE) AF: 0.621 AC: 675604 AN: 1088506

Other (OTH) AF: 0.564 AC: 33148 AN: 58814

GnomAD4 genome AF: 0.549 AC: 83493 AN: 152070 Hom.: 23974 Cov.: 32 AF XY: 0.537 AC XY: 39943 AN XY: 74346

African (AFR) AF: 0.508 AC: 21040 AN: 41456

American (AMR) AF: 0.477 AC: 7297 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.675 AC: 2341 AN: 3466

East Asian (EAS) AF: 0.0908 AC: 470 AN: 5178

South Asian (SAS) AF: 0.391 AC: 1883 AN: 4818

European-Finnish (FIN) AF: 0.570 AC: 6035 AN: 10582

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.626 AC: 42520 AN: 67950

Other (OTH) AF: 0.564 AC: 1192 AN: 2112

Alfa AF: 0.605 Hom.: 47408

Bravo AF: 0.541

Asia WGS AF: 0.278 AC: 967 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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. -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Gly2619Gly in Exon 41 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 46.7% (1513/3240) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs854772). -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 21, 2016

Eurofins Ntd Llc (ga)

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	-0.77
CADD	Benign	0.88
DANN	Benign	0.57
PhyloP100		0.10
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs854772; hg19: chr17-18055229; COSMIC: COSV52753944; COSMIC: COSV52753944;