rs201734915

chr17-18159953-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_016239.4(MYO15A):c.9322G>A(p.Val3108Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000117 in 1,613,958 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000081 (1 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 4.81

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03412676).
• BP6: Variant 17-18159953-G-A is Benign according to our data. Variant chr17-18159953-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164560.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.9322G>A	p.Val3108Ile	missense_variant	56/66	ENST00000647165.2
MYO15A	XM_017024715.3	c.9325G>A	p.Val3109Ile	missense_variant	54/64
MYO15A	XM_017024714.3	c.9262G>A	p.Val3088Ile	missense_variant	53/63

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.9322G>A	p.Val3108Ile	missense_variant	56/66		NM_016239.4	P1

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.000196 AC: 49 AN: 249474 Hom.: 1 AF XY: 0.000163 AC XY: 22 AN XY: 135342

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000814 AC: 119 AN: 1461844 Hom.: 1 Cov.: 32 AF XY: 0.0000853 AC XY: 62 AN XY: 727220

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000672

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152114 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74314

Gnomad4 AFR AF: 0.00145

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000960

Alfa AF: 0.000301 Hom.: 0

Bravo AF: 0.000468

ESP6500AA AF: 0.00142 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 10, 2014	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2023

The c.9322G>A (p.V3108I) alteration is located in exon 56 (coding exon 55) of the MYO15A gene. This alteration results from a G to A substitution at nucleotide position 9322, causing the valine (V) at amino acid position 3108 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 01, 2014

Val3108Ile in exon 56 of MYO15A: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, black flying fox, megabat, and aardvark have an isoleucine (Ile) at this p osition despite high nearby amino acid conservation. It has been identified in 0 .14% (6/4218) of African American chromosomes by the NHLBI Exome Sequencing Proj ect (http://evs.gs.washington.edu/EVS/; dbSNP rs201734915). -

MYO15A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 27, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	22
Dann	Benign	0.96
DEOGEN2	Benign	0.0058	T;T;T;.;.;.;.;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.73	T;.;T;T;T;T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.034	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.34	D
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Benign	0.31	T
Sift4G	Uncertain	0.010	D;D;.;T;.;T;T;T
Polyphen		0.018	.;B;B;.;.;.;.;.
Vest4		0.22
MVP		0.64
ClinPred		0.037	T
GERP RS		4.6
Varity_R		0.094
gMVP		0.033

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: rs201734915; hg19: chr17-18063267;