chr17-18135725-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS2BS1_Supporting

This summary comes from the ClinGen Evidence Repository: The c.4497G>T variant in MYO15A is a missense variant predicted to cause substitution of glutamic acid by aspartic acid at amino acid 1499. The filtering allele frequency of this variant in gnomAD v4.1 is 0.1325% in the Admixed American population, which is higher than the ClinGen Hearing Loss threshold of 0.07% for BS1_Supporting, and therefore meets this criterion (BS1_Supporting). The computational predictor REVEL gives a score of 0.448, which is neither above nor below the thresholds predicting a damaging or benign impact on MYO15A function (BP4 and PP3 not met). This variant has been identified in 1 proband with hearing loss with a variant of uncertain significance suspected in trans (Partners LMM internal data SCV000711130.2). The variant has also been detected in the homozygous state in three unaffected parents (BS2; GeneDx internal data SCV001982245.2). In summary, this variant meets criteria to be classified as likely benign for autosomal recessive nonsyndromic hearing based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: BS1_Supporting, BS2 (ClinGen Hearing Loss VCEP specifications version 2; 3/12/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8423917/MONDO:0019497/023

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 3 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:5B:3

Conservation

PhyloP100: 2.82

Publications

6 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: Likely_benign. The variant received -5 ACMG points.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

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.4497G>T	p.Glu1499Asp	missense	Exon 13 of 66	NP_057323.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.4497G>T	p.Glu1499Asp	missense	Exon 13 of 66	ENSP00000495481.1

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

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:

0.000705

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000798

AC:

199

AN:

249272

AF XY:

0.000717

show subpopulations

Gnomad AFR exome

AF:

0.000259

Gnomad AMR exome

AF:

0.00168

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00113

Gnomad OTH exome

AF:

0.00149

GnomAD4 exome

AF:

0.00108

AC:

1577

AN:

1461830

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

762

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.00186

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00129

AC:

1432

AN:

1111978

Other (OTH)

AF:

0.000894

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

157

235

314

392

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.000479

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41576

American (AMR)

AF:

0.000785

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000706

AC:

AN:

68030

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.000985

Hom.:

Bravo

AF:

0.000623

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000240

AC:

ESP6500EA

AF:

0.00142

AC:

ExAC

AF:

0.000810

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.00107

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Autosomal recessive nonsyndromic hearing loss 3 (2)

MYO15A-related disorder (1)

Nonsyndromic genetic hearing loss (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.83

M_CAP

Benign

0.077

MetaRNN

Benign

0.032

MetaSVM

Uncertain

0.57

MutationAssessor

Benign

1.3

PhyloP100

2.8

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.45

Sift

Benign

0.24

Sift4G

Uncertain

0.059

Polyphen

1.0

Vest4

0.52

MutPred

0.43

Loss of disorder (P = 0.1633)

MVP

0.89

ClinPred

0.055

GERP RS

4.2

Varity_R

0.24

gMVP

0.34

Mutation Taster

=75/25

polymorphism

(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

Computational scores

Splicing

Publications

Other links and lift over