17-18119978-ACCC-ACCCC

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_016239.4(MYO15A):c.1185dupC(p.Glu396ArgfsTer36) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,612,170 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E396E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

MYO15A
NM_016239.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: -1.21

Publications

9 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 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 17-18119978-A-AC is Pathogenic according to our data. Variant chr17-18119978-A-AC is described in ClinVar as Pathogenic. ClinVar VariationId is 228372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4 link	c.1185dupC	p.Glu396ArgfsTer36	frameshift_variant	Exon 2 of 66	ENST00000647165.2	NP_057323.3	Q9UKN7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 link	c.1185dupC	p.Glu396ArgfsTer36	frameshift_variant	Exon 2 of 66		NM_016239.4	ENSP00000495481.1		Q9UKN7-1
MYO15A	ENST00000583079.1 link	n.818dupC		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

AF:

0.0000265

AC:

AN:

150760

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000490

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:

0.0000148

Gnomad OTH

AF:

0.000482

GnomAD2 exomes

AF:

0.0000643

AC:

AN:

248922

AF XY:

0.0000517

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000996

Gnomad EAS exome

AF:

0.000334

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000798

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000328

AC:

AN:

1461298

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

726934

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.000277

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000757

AC:

AN:

52842

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000270

AC:

AN:

1112004

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

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:

0.0000265

AC:

AN:

150872

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73670

show subpopulations

African (AFR)

AF:

0.0000488

AC:

AN:

40942

American (AMR)

AF:

0.00

AC:

AN:

15208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5088

South Asian (SAS)

AF:

0.00

AC:

AN:

4760

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10432

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67680

Other (OTH)

AF:

0.000477

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 3

Pathogenic:5

May 22, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000228372 / PMID: 22245518 / 3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Molecular Diagnosis Center for Deafness

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 28, 2019

Laboratory of Molecular Genetics, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

The individual with congenital NSHL carried single frameshift variant in MYO15A as well as single missense variant in the different locus in the same gene. They were segregated with the disease in his family and patient was a sporadic case in it. NSHL carried by the patient was categorized as a type of severe and profound hearing loss based on audiogram. -

Jul 31, 2018

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A heterozygous frameshift duplication variant, NM_016239.3(MYO15A):c.1185dupC, has been identified in exon 2 of 66 of the MYO15A gene. This duplication is predicted to create a frameshift starting at amino acid position 396, introducing a stop codon 36 residues downstream (NP_057323.3(MYO15A):p.(Glu396Argfs*36)). This variant is predicted to result in loss of protein function either through truncation (including the loss of multiple domains) or nonsense-mediated decay, which is a reported mechanism of pathogenicity for this gene. The variant is present in the gnomAD database at a frequency of 0.0047% (13 heterozygotes and 0 homozygotes). It has been previously described as pathogenic and segregated with disease in two families (Bashir R. et al. (2012), Miyagawa M. et al. (2015)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -

Feb 26, 2025

Clinical Genomics, G42 Labs

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1185dup, p.(Glu396fs*36) is a frameshift variant in the MYO15A gene, thereby leading to premature truncation of the protein at 36 amino acids downstream to codon 396. Allele frequency of this variant in gnomAD population database is 0.003% (4/150872 alleles, no homozygotes). Six clinical laboratories have classified this variant as pathogenic (Variation ID: VCV000228372.35). This premature translational stop signal has been observed in individual(s) with nonsyndromic deafness (PMID: 22245518, 31827275). Based on the above reasons, this variant is classified as pathogenic. ACMG Criteria: PVS1, PM2, PP5 - Pathogenic -

not provided

Pathogenic:2

Aug 23, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 37734845, 31827275, 33784549, 22245518, 35346193, 35248088) -

Feb 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Glu396Argfs*36) in the MYO15A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYO15A are known to be pathogenic (PMID: 17546645). This variant is present in population databases (rs746288259, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with nonsyndromic deafness (PMID: 22245518, 31827275). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 228372). For these reasons, this variant has been classified as Pathogenic. -

Rare genetic deafness

Pathogenic:1

Jun 30, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Glu396fs variant in MYO15A has been previously reported in two individuals with hearing loss including one homozygote state and segregated with disease in 2 affected siblings (Bashir 2012, LMM data). This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at posit ion 396 and leads to a premature termination codon 36 amino acids downstream. Th is alteration is then predicted to lead to a truncated or absent protein. In sum mary, this variant meets our criteria to be classified as pathogenic for hearing loss in an autosomal recessive manner based on the predicted impact of the vari ant and segregation evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.2

Mutation Taster

=1/199

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over