rs854778

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_016239.4(MYO15A):c.5826-12A>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.734 in 1,610,714 control chromosomes in the GnomAD database, including 436,547 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.75 ( 43442 hom., cov: 30)

Exomes 𝑓: 0.73 ( 393105 hom. )

Consequence

MYO15A
NM_016239.4 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00001800

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.446

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 17-18142744-A-C is Benign according to our data. Variant chr17-18142744-A-C is described in ClinVar as [Benign]. Clinvar id is 45751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18142744-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.796 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4 linkuse as main transcript	c.5826-12A>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 linkuse as main transcript	c.5826-12A>C		splice_polypyrimidine_tract_variant, intron_variant			NM_016239.4	ENSP00000495481	P1	Q9UKN7-1

Frequencies

GnomAD3 genomes

AF:

0.753

AC:

114275

AN:

151696

Hom.:

43374

Cov.:

show subpopulations

Gnomad AFR

AF:

0.803

Gnomad AMI

AF:

0.656

Gnomad AMR

AF:

0.762

Gnomad ASJ

AF:

0.800

Gnomad EAS

AF:

0.601

Gnomad SAS

AF:

0.562

Gnomad FIN

AF:

0.752

Gnomad MID

AF:

0.759

Gnomad NFE

AF:

0.745

Gnomad OTH

AF:

0.758

GnomAD3 exomes

AF:

0.717

AC:

175518

AN:

244836

Hom.:

63838

AF XY:

0.707

AC XY:

94074

AN XY:

133036

show subpopulations

Gnomad AFR exome

AF:

0.796

Gnomad AMR exome

AF:

0.768

Gnomad ASJ exome

AF:

0.806

Gnomad EAS exome

AF:

0.600

Gnomad SAS exome

AF:

0.559

Gnomad FIN exome

AF:

0.753

Gnomad NFE exome

AF:

0.737

Gnomad OTH exome

AF:

0.736

GnomAD4 exome

AF:

0.732

AC:

1067674

AN:

1458900

Hom.:

393105

Cov.:

AF XY:

0.726

AC XY:

527027

AN XY:

725620

show subpopulations

Gnomad4 AFR exome

AF:

0.809

Gnomad4 AMR exome

AF:

0.767

Gnomad4 ASJ exome

AF:

0.807

Gnomad4 EAS exome

AF:

0.598

Gnomad4 SAS exome

AF:

0.568

Gnomad4 FIN exome

AF:

0.757

Gnomad4 NFE exome

AF:

0.742

Gnomad4 OTH exome

AF:

0.737

GnomAD4 genome

AF:

0.754

AC:

114403

AN:

151814

Hom.:

43442

Cov.:

AF XY:

0.748

AC XY:

55535

AN XY:

74212

show subpopulations

Gnomad4 AFR

AF:

0.803

Gnomad4 AMR

AF:

0.762

Gnomad4 ASJ

AF:

0.800

Gnomad4 EAS

AF:

0.601

Gnomad4 SAS

AF:

0.562

Gnomad4 FIN

AF:

0.752

Gnomad4 NFE

AF:

0.745

Gnomad4 OTH

AF:

0.759

Alfa

AF:

0.762

Hom.:

8160

Bravo

AF:

0.758

Asia WGS

AF:

0.592

AC:

2060

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	5826-12A>C in Intron 24 of MYO15A: This variant is not expected to have clinical significance because it has been identified in 24.7% (1665/6752) of European Am erican chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs854778). -

Autosomal recessive nonsyndromic hearing loss 3

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

4.9

DANN

Benign

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000018

dbscSNV1_RF

Benign

0.0020

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