rs763975867

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PVS1PM2PP3_StrongPP5

The NM_016239.4(MYO15A):c.6764+2T>A variant causes a splice donor change. The variant allele was found at a frequency of 0.000127 in 1,551,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

MYO15A
NM_016239.4 splice_donor

Scores

Splicing: ADA: 1.000

Clinical Significance

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

Conservation

PhyloP100: 5.87

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 15 ACMG points.

PVS1

Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

PP5

Variant 17-18148570-T-A is Pathogenic according to our data. Variant chr17-18148570-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 289237.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Pathogenic=3, Uncertain_significance=1}. Variant chr17-18148570-T-A is described in Lovd as [Likely_pathogenic]. Variant chr17-18148570-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
MYO15A	NM_016239.4 linkuse as main transcript	c.6764+2T>A	splice_donor_variant	ENST00000647165.2
MYO15A	XM_017024714.3 linkuse as main transcript	c.6704+2T>A	splice_donor_variant
MYO15A	XM_017024715.3 linkuse as main transcript	c.6767+2T>A	splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2 linkuse as main transcript	c.6764+2T>A		splice_donor_variant			NM_016239.4	P1	Q9UKN7-1
MYO15A	ENST00000578999.1 linkuse as main transcript	n.277-191T>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000790

AC:

AN:

151970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000177

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000194

AC:

AN:

154764

Hom.:

AF XY:

0.0000122

AC XY:

AN XY:

81898

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000497

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000132

AC:

185

AN:

1399466

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

690288

show subpopulations

Gnomad4 AFR exome

AF:

0.0000633

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000162

Gnomad4 OTH exome

AF:

0.000138

GnomAD4 genome

AF:

0.0000790

AC:

AN:

151970

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74218

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000177

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000120

Hom.:

Bravo

AF:

0.0000831

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2023	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24123792, 27375115, 26969326, 31827275, 32658404) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 05, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 15, 2023	This sequence change affects a donor splice site in intron 32 of the MYO15A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYO15A are known to be pathogenic (PMID: 17546645). This variant is present in population databases (rs763975867, gnomAD 0.008%). Disruption of this splice site has been observed in individuals with deafness (PMID: 24123792, 31827275). ClinVar contains an entry for this variant (Variation ID: 289237). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MYO15A: PVS1, PM2, PM3 -

Autosomal recessive nonsyndromic hearing loss 3

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 19, 2017	The MYO15A c.6764+2T>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. This variant has been reported in two studies and identified in two individuals with congenital hearing loss. One individual had the variant in a compound heterozygous state with a second splice variant (Sloan-Heggen et al. 2016). The other individual had the c.6764+2T>A variant along with two missense variants where phase was not determined (Neveling et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.000083 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the limited clinical evidence and due to the potential impact of splice donor variants, the c.6764+2T>A variant is classified as a variant of unknown significance, but suspicious for pathogenicity for autosomal recessive hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as 4-likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness, autosomal recessive 3 (MIM#600316). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 12 heterozygotes, 0 homozygotes). (SP) 0508 - In silico predictions for abnormal splicing are inconclusive. (I) 0705 - No comparable canonical splice variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in individuals with hearing loss and confirmed to be compound heterozygous in two of these individuals (ClinVar; PMIDs: 24123792, 26969326). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 04, 2019

The c.6764+2T>A variant in MYO15A has been reported in 3 individuals with hearin g loss (Neveling 2013, LMM data). However, only one of these individuals carried a second variant in MYO15A (Neveling 2013). The c.6764+2T>A variant has also be en identified in 0.0079% (6/75702) of European chromosomes by gnomAD (http://gno mad.broadinstitute.org). Although this variant has been seen in the general popu lation, its frequency is low enough to be consistent with a recessive carrier fr equency. This variant occurs in the invariant region (+/- 1,2) of the splice con sensus sequence and is predicted to cause altered splicing leading to an abnorma l or absent protein. Loss of MYO15A function is an established disease mechanism in autosomal recessive hearing loss. In summary, although additional studies ar e required to fully establish its clinical significance, the c.6764+2T>A variant meets criteria to be classified as likely pathogenic for autosomal recessive he aring loss. ACMG/AMP criteria applied: PVS1, PM2. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

GERP RS

4.3

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.44

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.44

Position offset: -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