rs182332665

Positions:

• chr17-18178850-A-G

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.10573A>G​(p.Ser3525Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00276 in 1,613,360 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (114 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 9.08

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008612871).
• BP6: Variant 17-18178850-A-G is Benign according to our data. Variant chr17-18178850-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 226775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00281 (427/152084) while in subpopulation SAS AF= 0.0387 (186/4802). AF 95% confidence interval is 0.0342. There are 7 homozygotes in gnomad4. There are 264 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.10573A>G	p.Ser3525Gly	missense_variant	66/66	ENST00000647165.2	NP_057323.3
MYO15A	XM_017024715.3	c.10576A>G	p.Ser3526Gly	missense_variant	64/64		XP_016880204.1
MYO15A	XM_017024714.3	c.10513A>G	p.Ser3505Gly	missense_variant	63/63		XP_016880203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.10573A>G	p.Ser3525Gly	missense_variant	66/66		NM_016239.4	ENSP00000495481	P1
	ENST00000577847.1	n.272-485T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 430 AN: 151966 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000822

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0389

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00642 AC: 1581 AN: 246396 Hom.: 35 AF XY: 0.00769 AC XY: 1031 AN XY: 134012

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.0115

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000334

Gnomad SAS exome AF: 0.0372

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000542

Gnomad OTH exome AF: 0.00465

GnomAD4 exome AF: 0.00275 AC: 4024 AN: 1461276 Hom.: 114 Cov.: 31 AF XY: 0.00376 AC XY: 2732 AN XY: 726940

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.0125

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0366

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.00368

GnomAD4 genome AF: 0.00281 AC: 427 AN: 152084 Hom.: 7 Cov.: 32 AF XY: 0.00355 AC XY: 264 AN XY: 74338

Gnomad4 AFR AF: 0.000820

Gnomad4 AMR AF: 0.0120

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0387

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00617

Alfa AF: 0.000243 Hom.: 0

Bravo AF: 0.00339

ESP6500AA AF: 0.000705 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00634 AC: 768

Asia WGS AF: 0.0160 AC: 57 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	MYO15A: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 18, 2015	p.Ser3525Gly in exon 66 of MYO15A: This variant is not expected to have clinical significance because it has been identified in 3.6% (589/16462; 18 homozygotes) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://ex ac.broadinstitute.org; dbSNP rs182332665). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 23, 2017	- -

Autosomal recessive nonsyndromic hearing loss 3 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T;T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;.;T
MetaRNN	Benign	0.0086	T;T;T
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.8	.;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.7	.;N;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.0020	.;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	.;D;D
Vest4		0.41
MVP		0.94
ClinPred		0.035	T
GERP RS		5.6
Varity_R		0.38
gMVP		0.47

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: rs182332665; hg19: chr17-18082164;