rs200930743

Positions:

chr17-18153792-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_016239.4(MYO15A):c.7984C>G(p.Leu2662Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000654 in 1,613,588 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.00053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00067 ( 2 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 1.05

Variant links:

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 links:

LOC105371567 (HGNC:):

LOC105371567 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04865986).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MYO15A	NM_016239.4 linkuse as main transcript	c.7984C>G	p.Leu2662Val	missense_variant	43/66	ENST00000647165.2
LOC105371567	XR_001752809.1 linkuse as main transcript	n.367+23G>C		intron_variant, non_coding_transcript_variant
MYO15A	XM_017024715.3 linkuse as main transcript	c.7987C>G	p.Leu2663Val	missense_variant	41/64
MYO15A	XM_017024714.3 linkuse as main transcript	c.7924C>G	p.Leu2642Val	missense_variant	40/63

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2 linkuse as main transcript	c.7984C>G	p.Leu2662Val	missense_variant	43/66		NM_016239.4	P1	Q9UKN7-1

Frequencies

GnomAD3 genomes

AF:

0.000532

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00103

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000955

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000583

AC:

145

AN:

248654

Hom.:

AF XY:

0.000503

AC XY:

AN XY:

135214

show subpopulations

Gnomad AFR exome

AF:

0.000195

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000928

Gnomad NFE exome

AF:

0.00104

Gnomad OTH exome

AF:

0.000827

GnomAD4 exome

AF:

0.000667

AC:

974

AN:

1461348

Hom.:

Cov.:

AF XY:

0.000602

AC XY:

438

AN XY:

726982

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000868

Gnomad4 NFE exome

AF:

0.000811

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000532

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000592

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00103

Gnomad4 NFE

AF:

0.000955

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000690

Hom.:

Bravo

AF:

0.000510

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000853

AC:

ExAC

AF:

0.000670

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MYO15A p.Leu2662Val variant was not identified in the literature but was identified in dbSNP (ID: rs200930743), ClinVar (classified as a VUS by EGL Genetic Diagnostics and Laboratory for Molecular Medicine) and LOVD 3.0 (classified as a VUS). The variant was identified in control databases in 164 of 280048 chromosomes (0 homozygous) at a frequency of 0.000586 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 131 of 128014 chromosomes (freq: 0.001023), European (Finnish) in 23 of 25032 chromosomes (freq: 0.000919), Other in 6 of 7134 chromosomes (freq: 0.000841) and African in 4 of 24074 chromosomes (freq: 0.000166), but was not observed in the Latino, Ashkenazi Jewish, East Asian or South Asian populations. The p.Leu2662 residue is conserved across mammals and other organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 21, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 05, 2019

proposed classification - variant undergoing re-assessment, contact laboratory -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 19, 2024

The c.7984C>G (p.L2662V) alteration is located in exon 43 (coding exon 42) of the MYO15A gene. This alteration results from a C to G substitution at nucleotide position 7984, causing the leucine (L) at amino acid position 2662 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Autosomal recessive nonsyndromic hearing loss 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Hearing impairment

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 12, 2021

PM2_Supporting, BP4_Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.022

T;T;T

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.73

T;.;T

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.049

T;T;T

MetaSVM

Uncertain

-0.12

MutationTaster

Benign

0.86

D;D

PrimateAI

Benign

0.37

Sift4G

Benign

0.13

T;T;.

Polyphen

0.82

.;P;P

Vest4

0.20

MVP

0.71

ClinPred

0.066

GERP RS

3.1

Varity_R

0.15

gMVP

0.29

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over