rs200249886

chr17-18171736-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_016239.4(MYO15A):c.10181C>T(p.Ala3394Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000281 in 1,612,256 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A3394A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (1 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 7.82

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_016239.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.10181C>T	p.Ala3394Val	missense_variant	63/66	ENST00000647165.2
MYO15A	XM_017024715.3	c.10184C>T	p.Ala3395Val	missense_variant	61/64
MYO15A	XM_017024714.3	c.10121C>T	p.Ala3374Val	missense_variant	60/63

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.10181C>T	p.Ala3394Val	missense_variant	63/66		NM_016239.4	P1

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000399 AC: 98 AN: 245468 Hom.: 0 AF XY: 0.000419 AC XY: 56 AN XY: 133746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00240

Gnomad EAS exome AF: 0.0000559

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.0000504

Gnomad NFE exome AF: 0.000591

Gnomad OTH exome AF: 0.000667

GnomAD4 exome AF: 0.000287 AC: 419 AN: 1459922 Hom.: 1 Cov.: 32 AF XY: 0.000295 AC XY: 214 AN XY: 726350

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00199

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000776

Gnomad4 NFE exome AF: 0.000308

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74486

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000331 Hom.: 0

Bravo AF: 0.000219

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000601 AC: 5

ExAC AF: 0.000289 AC: 35

EpiCase AF: 0.000545

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 3 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 09, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2017	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 15, 2014

The p.Ala3394Val variant in MYO15A has not been previously reported in individua ls with hearing loss, but has been identified in 0.05% (35/64,726) of European c hromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org; dbSNP rs200249886). Although this variant has been seen in the general populatio n, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine path ogenicity. In summary, the clinical significance of the p.Ala3394Val variant is uncertain. -

Hearing impairment Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PS1_Supporting, PM2_Supporting, PP3_Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.18
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Benign	0.030	T;T;T;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;.;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.095	T;T;T;T;T
MetaSVM	Pathogenic	0.89	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
Sift4G	Uncertain	0.0090	D;D;.;D;.
Polyphen		1.0	.;D;D;.;.
Vest4		0.60
MVP		0.74
ClinPred		0.35	T
GERP RS		5.7
Varity_R		0.38
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.73		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200249886; hg19: chr17-18075050; COSMIC: COSV99232172; COSMIC: COSV99232172;