17-18148859-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S2288S) has been classified as Likely benign.

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

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MYO15A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 322158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016239.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	NM_016239.4	MANE Select	c.6863C>T	p.Ser2288Leu	missense	Exon 33 of 66	NP_057323.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.6863C>T	p.Ser2288Leu	missense	Exon 33 of 66	ENSP00000495481.1
	MYO15A	ENST00000578999.1	TSL:5	n.375C>T		non_coding_transcript_exon	Exon 3 of 4

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

GnomAD2 exomes

AF:

0.00000852

AC:

AN:

234646

AF XY:

0.00

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 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

African (AFR)

AF:

0.00

AC:

AN:

33362

American (AMR)

AF:

0.00

AC:

AN:

43966

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25946

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39460

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84876

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52748

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00000721

AC:

AN:

1108922

Other (OTH)

AF:

0.00

AC:

AN:

60096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41430

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Nov 20, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Feb 13, 2025

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:2

Nov 03, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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)

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYO15A: PM2, PM3, PM5

Rare genetic deafness

Pathogenic:1

Feb 05, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.78

MetaSVM

Uncertain

0.46

MutationAssessor

Uncertain

2.9

PhyloP100

4.8

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0090

Polyphen

0.98

Vest4

0.32

MutPred

0.60

Loss of helix (P = 0.0376)

MVP

0.88

ClinPred

0.98

GERP RS

4.5

Varity_R

0.48

gMVP

0.90

Mutation Taster

=59/41

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over