17-18148859-C-T

Position:

chr17-18148859-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_016239.4(MYO15A):c.6863C>T(p.Ser2288Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000995 in 1,607,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 4.81

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.784

PP5

Variant 17-18148859-C-T is Pathogenic according to our data. Variant chr17-18148859-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 322158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18148859-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4 link	c.6863C>T	p.Ser2288Leu	missense_variant	33/66	ENST00000647165.2	NP_057323.3	Q9UKN7-1
MYO15A	XM_017024715.3 link	c.6866C>T	p.Ser2289Leu	missense_variant	31/64		XP_016880204.1
MYO15A	XM_017024714.3 link	c.6803C>T	p.Ser2268Leu	missense_variant	30/63		XP_016880203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 link	c.6863C>T	p.Ser2288Leu	missense_variant	33/66		NM_016239.4	ENSP00000495481.1		Q9UKN7-1
MYO15A	ENST00000578999.1 link	n.375C>T		non_coding_transcript_exon_variant	3/4	5

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000852

AC:

AN:

234646

Hom.:

AF XY:

0.00

AC XY:

AN XY:

127646

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000577

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000944

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000687

AC:

AN:

1455132

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

723176

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000721

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 3

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 20, 2024	Variant summary: MYO15A c.6863C>T (p.Ser2288Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-06 in 234646 control chromosomes. c.6863C>T has been reported in the literature in compound heterozygous individuals affected with Autosomal Recessive Nonsyndromic Hearing Loss, including at least one case where it was reported in trans with a pathogenic variant (e.g. Wang_2021, Wonkam_2022, Wu_2022, Chen_2022, Zeng_2022, Pan_2022) . These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34974475, 34744965, 35440622, 35982127, 36568381, 35640668). ClinVar contains an entry for this variant (Variation ID: 322158). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 13, 2025	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	MYO15A: PM2, PM3, PM5 -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2023	Identified with a second MYO15A variant (phase unknown) in patients with childhood-onset bilateral sensorineural hearing loss referred for genetic testing at GeneDx and in published literature (PMID: 35440622); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34974475, 35440622) -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 05, 2024

The p.Ser2288Leu variant in MYO15A has been identified in the compound heterozygous state in at least 8 individuals with hearing loss (Wonkam 2022 PMID: 35440622, Chen 2022 PMID: 34974475, Wu 2022 PMID: 35982127, LMM internal data), 5 of whom had a second disease causing variant in the MYO15A gene, including 4 confirmed to be in trans. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 322158) and has been identified in 0.005% (1/18344) East Asian chromosomes, 0.004% (1/22666) African chromosomes, and 0.004% (3/74792) African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org/, v.4.0.0). This low frequency is consistent with the carrier frequency for recessive hearing loss. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2_Supporting, PS4_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;D;D

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

D;.;D

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.78

D;D;D

MetaSVM

Uncertain

0.46

MutationAssessor

Uncertain

2.9

.;M;M

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-5.0

.;D;.

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0020

.;D;.

Sift4G

Uncertain

0.0090

D;D;.

Polyphen

0.98

.;D;D

Vest4

0.32

MutPred

0.60

Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);

MVP

0.88

ClinPred

0.98

GERP RS

4.5

Varity_R

0.48

gMVP

0.90

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