chr17-18118568-T-C

Variant names:

• chr17-18118568-T-C
• rs854817
• NM_016239.4:c.-219-14T>C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_016239.4(MYO15A):​c.-219-14T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.426 in 595,858 control chromosomes in the GnomAD database, including 60,889 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (18096 hom., cov: 33)
  • Exomes 𝑓: 0.41 (42793 hom.)
• Consequence: MYO15A NM_016239.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.962

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 17-18118568-T-C is Benign according to our data. Variant chr17-18118568-T-C is described in ClinVar as [Benign]. Clinvar id is 322102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.687 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.-219-14T>C		intron_variant	Intron 1 of 65	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.-219-14T>C		intron_variant	Intron 1 of 65		NM_016239.4	ENSP00000495481.1

Frequencies

GnomAD3 genomes AF: 0.463 AC: 70366 AN: 152016 Hom.: 18045 Cov.: 33

Gnomad AFR AF: 0.655

Gnomad AMI AF: 0.417

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.419

Gnomad EAS AF: 0.635

Gnomad SAS AF: 0.707

Gnomad FIN AF: 0.415

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.434

GnomAD4 exome AF: 0.413 AC: 183388 AN: 443724 Hom.: 42793 Cov.: 5 AF XY: 0.428 AC XY: 99513 AN XY: 232494

Gnomad4 AFR exome AF: 0.667

Gnomad4 AMR exome AF: 0.498

Gnomad4 ASJ exome AF: 0.424

Gnomad4 EAS exome AF: 0.657

Gnomad4 SAS exome AF: 0.703

Gnomad4 FIN exome AF: 0.382

Gnomad4 NFE exome AF: 0.324

Gnomad4 OTH exome AF: 0.417

GnomAD4 genome AF: 0.463 AC: 70471 AN: 152134 Hom.: 18096 Cov.: 33 AF XY: 0.473 AC XY: 35186 AN XY: 74374

Gnomad4 AFR AF: 0.655

Gnomad4 AMR AF: 0.486

Gnomad4 ASJ AF: 0.419

Gnomad4 EAS AF: 0.636

Gnomad4 SAS AF: 0.707

Gnomad4 FIN AF: 0.415

Gnomad4 NFE AF: 0.322

Gnomad4 OTH AF: 0.433

Alfa AF: 0.374 Hom.: 3596

Bravo AF: 0.472

Asia WGS AF: 0.662 AC: 2300 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 3 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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

Other links and lift over

dbSNP: rs854817; hg19: chr17-18021882; COSMIC: COSV52764452; COSMIC: COSV52764452;