17-18153901-C-G

Variant names:

• chr17-18153901-C-G
• rs9916193
• NM_016239.4:c.8088+5C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016239.4(MYO15A):​c.8088+5C>G variant causes a splice region, 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_region, intron
• Scores: Splicing: ADA: 0.00009153
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.49
• Publications: 15 publications found

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

LOC105371567 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 226789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.8088+5C>G		splice_region_variant, intron_variant	Intron 43 of 65	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.8088+5C>G		splice_region_variant, intron_variant	Intron 43 of 65		NM_016239.4	ENSP00000495481.1

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36360 AN: 151832 Hom.: 5017 Cov.: 32

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

GnomAD2 exomes AF: 0.188 AC: 46606 AN: 248254 AF XY: 0.191

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 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.: 54 AF XY: 0.198 AC XY: 143567 AN XY: 726860

African (AFR) AF: 0.373 AC: 12470 AN: 33470

American (AMR) AF: 0.128 AC: 5736 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 7230 AN: 26132

East Asian (EAS) AF: 0.00285 AC: 113 AN: 39700

South Asian (SAS) AF: 0.191 AC: 16434 AN: 86248

European-Finnish (FIN) AF: 0.145 AC: 7668 AN: 52782

Middle Eastern (MID) AF: 0.342 AC: 1971 AN: 5768

European-Non Finnish (NFE) AF: 0.201 AC: 223544 AN: 1111946

Other (OTH) AF: 0.207 AC: 12526 AN: 60378

GnomAD4 genome AF: 0.240 AC: 36446 AN: 151950 Hom.: 5046 Cov.: 32 AF XY: 0.233 AC XY: 17277 AN XY: 74268

African (AFR) AF: 0.366 AC: 15150 AN: 41408

American (AMR) AF: 0.190 AC: 2902 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 966 AN: 3470

East Asian (EAS) AF: 0.00853 AC: 44 AN: 5160

South Asian (SAS) AF: 0.176 AC: 844 AN: 4806

European-Finnish (FIN) AF: 0.149 AC: 1570 AN: 10558

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.209 AC: 14205 AN: 67962

Other (OTH) AF: 0.257 AC: 541 AN: 2102

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

Submissions by phenotype

not specified Benign:5

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 3 Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.4
DANN	Benign	0.45
PhyloP100		-1.5
PromoterAI		0.0073	Neutral
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9916193; hg19: chr17-18057215;