rs9916193

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.8088+5C>G variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 1,613,094 control chromosomes in the GnomAD database, including 35,467 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 5046 hom., cov: 32)

Exomes 𝑓: 0.20 ( 30421 hom. )

Consequence

MYO15A
NM_016239.4 splice_donor_5th_base, intron

Scores

Splicing: ADA: 0.00009153

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.49

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:

LOC105371567 (HGNC:):

LOC105371567 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=-0.83).

BP6

Variant 17-18153901-C-G is Benign according to our data. Variant chr17-18153901-C-G is described in ClinVar as [Benign]. Clinvar id is 226789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18153901-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.361 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.8088+5C>G		splice_donor_5th_base_variant, intron_variant		ENST00000647165.2	NP_057323.3
LOC105371567	XR_001752809.1 linkuse as main transcript	n.298-17G>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 linkuse as main transcript	c.8088+5C>G		splice_donor_5th_base_variant, intron_variant			NM_016239.4	ENSP00000495481	P1	Q9UKN7-1

Frequencies

GnomAD3 genomes

AF:

0.239

AC:

36360

AN:

151832

Hom.:

5017

Cov.:

show subpopulations

Gnomad AFR

AF:

0.365

Gnomad AMI

AF:

0.147

Gnomad AMR

AF:

0.190

Gnomad ASJ

AF:

0.278

Gnomad EAS

AF:

0.00851

Gnomad SAS

AF:

0.174

Gnomad FIN

AF:

0.149

Gnomad MID

AF:

0.313

Gnomad NFE

AF:

0.209

Gnomad OTH

AF:

0.255

GnomAD3 exomes

AF:

0.188

AC:

46606

AN:

248254

Hom.:

5148

AF XY:

0.191

AC XY:

25829

AN XY:

135136

show subpopulations

Gnomad AFR exome

AF:

0.367

Gnomad AMR exome

AF:

0.117

Gnomad ASJ exome

AF:

0.270

Gnomad EAS exome

AF:

0.00457

Gnomad SAS exome

AF:

0.184

Gnomad FIN exome

AF:

0.146

Gnomad NFE exome

AF:

0.215

Gnomad OTH exome

AF:

0.210

GnomAD4 exome

AF:

0.197

AC:

287692

AN:

1461144

Hom.:

30421

Cov.:

AF XY:

0.198

AC XY:

143567

AN XY:

726860

show subpopulations

Gnomad4 AFR exome

AF:

0.373

Gnomad4 AMR exome

AF:

0.128

Gnomad4 ASJ exome

AF:

0.277

Gnomad4 EAS exome

AF:

0.00285

Gnomad4 SAS exome

AF:

0.191

Gnomad4 FIN exome

AF:

0.145

Gnomad4 NFE exome

AF:

0.201

Gnomad4 OTH exome

AF:

0.207

GnomAD4 genome

AF:

0.240

AC:

36446

AN:

151950

Hom.:

5046

Cov.:

AF XY:

0.233

AC XY:

17277

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.366

Gnomad4 AMR

AF:

0.190

Gnomad4 ASJ

AF:

0.278

Gnomad4 EAS

AF:

0.00853

Gnomad4 SAS

AF:

0.176

Gnomad4 FIN

AF:

0.149

Gnomad4 NFE

AF:

0.209

Gnomad4 OTH

AF:

0.257

Alfa

AF:

0.182

Hom.:

912

Bravo

AF:

0.250

Asia WGS

AF:

0.120

AC:

418

AN:

3476

EpiCase

AF:

0.221

EpiControl

AF:

0.229

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	8088+5C>G in Intron 43 of MYO15A: This variant is not expected to have clinical significance because it has been identified in 34.7% (1048/3018) of African Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs9916193). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive nonsyndromic hearing loss 3

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided

Benign:2

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

-0.83

CADD

Benign

3.4

DANN

Benign

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000092

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