rs114274755

chr17-18148792-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016239.4(MYO15A):c.6796G>A(p.Val2266Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00416 in 1,603,676 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (28 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.35

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00869599).
• BP6: Variant 17-18148792-G-A is Benign according to our data. Variant chr17-18148792-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 178619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00787 (1198/152316) while in subpopulation AFR AF= 0.0183 (761/41562). AF 95% confidence interval is 0.0172. There are 7 homozygotes in gnomad4. There are 556 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.6796G>A	p.Val2266Met	missense_variant	33/66	ENST00000647165.2
MYO15A	XM_017024715.3	c.6799G>A	p.Val2267Met	missense_variant	31/64
MYO15A	XM_017024714.3	c.6736G>A	p.Val2246Met	missense_variant	30/63

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.6796G>A	p.Val2266Met	missense_variant	33/66		NM_016239.4	P1
MYO15A	ENST00000578999.1	n.308G>A		non_coding_transcript_exon_variant	3/4	5

Frequencies

GnomAD3 genomes AF: 0.00777 AC: 1183 AN: 152198 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0183

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00366

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00434 AC: 993 AN: 229054 Hom.: 4 AF XY: 0.00437 AC XY: 546 AN XY: 124908

Gnomad AFR exome AF: 0.0189

Gnomad AMR exome AF: 0.00264

Gnomad ASJ exome AF: 0.00187

Gnomad EAS exome AF: 0.00146

Gnomad SAS exome AF: 0.00729

Gnomad FIN exome AF: 0.00229

Gnomad NFE exome AF: 0.00323

Gnomad OTH exome AF: 0.00465

GnomAD4 exome AF: 0.00377 AC: 5474 AN: 1451360 Hom.: 28 Cov.: 34 AF XY: 0.00390 AC XY: 2810 AN XY: 721160

Gnomad4 AFR exome AF: 0.0191

Gnomad4 AMR exome AF: 0.00269

Gnomad4 ASJ exome AF: 0.00181

Gnomad4 EAS exome AF: 0.00117

Gnomad4 SAS exome AF: 0.00792

Gnomad4 FIN exome AF: 0.00175

Gnomad4 NFE exome AF: 0.00309

Gnomad4 OTH exome AF: 0.00624

GnomAD4 genome AF: 0.00787 AC: 1198 AN: 152316 Hom.: 7 Cov.: 32 AF XY: 0.00747 AC XY: 556 AN XY: 74470

Gnomad4 AFR AF: 0.0183

Gnomad4 AMR AF: 0.00444

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00425

Gnomad4 SAS AF: 0.00829

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.00366

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00499 Hom.: 26

Bravo AF: 0.00826

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.0140 AC: 58

ESP6500EA AF: 0.00345 AC: 29

ExAC AF: 0.00432 AC: 522

Asia WGS AF: 0.0200 AC: 71 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 03, 2019	This variant is associated with the following publications: (PMID: 26399936, 27375115, 25262649, 22995991, 20981092, 17546645, 22245518, 19309289, 26186295, 30245029, 30953472) -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 05, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	MYO15A: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Val2266Met in Exon 33 of MYO15A: This variant is not expected to have clinical s ignificance because it has been identified in 1.4% (49/3462) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs114274755). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 27, 2015	- -

Autosomal recessive nonsyndromic hearing loss 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.16	T;D;D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T;.;T
MetaRNN	Benign	0.0087	T;T;T
MetaSVM	Pathogenic	0.80	D
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.47	T
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	.;D;D
Vest4		0.26
MVP		0.79
ClinPred		0.019	T
GERP RS		4.3
Varity_R		0.21
gMVP		0.77

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: rs114274755; hg19: chr17-18052106; COSMIC: COSV105857901; COSMIC: COSV105857901;