rs1415858976

Variant names:

• chr17-18149550-CTT-C
• rs1415858976
• NM_016239.4:c.7184_7185delTT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_016239.4(MYO15A):​c.7184_7185delTT​(p.Phe2395fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000144 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. F2395F) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: MYO15A NM_016239.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.49

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]

LOC124903944 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-18149550-CTT-C is Pathogenic according to our data. Variant chr17-18149550-CTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 451626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.7184_7185delTT	p.Phe2395fs	frameshift_variant	Exon 35 of 66	ENST00000647165.2	NP_057323.3
MYO15A	XM_017024715.3	c.7187_7188delTT	p.Phe2396fs	frameshift_variant	Exon 33 of 64		XP_016880204.1
MYO15A	XM_017024714.3	c.7124_7125delTT	p.Phe2375fs	frameshift_variant	Exon 32 of 63		XP_016880203.1
LOC124903944	XR_007065652.1	n.*27_*28delAA		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.7184_7185delTT	p.Phe2395fs	frameshift_variant	Exon 35 of 66		NM_016239.4	ENSP00000495481.1
MYO15A	ENST00000578999.1	n.805_806delTT		non_coding_transcript_exon_variant	Exon 4 of 4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000801 AC: 2 AN: 249574 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135404

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461878 Hom.: 0 AF XY: 0.0000110 AC XY: 8 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

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: 0.0000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Nov 20, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Phe2395*) in the MYO15A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYO15A are known to be pathogenic (PMID: 17546645). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with MYO15A-related conditions. ClinVar contains an entry for this variant (Variation ID: 451626). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Dec 02, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

MYO15A-related disorder Pathogenic:1

Aug 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MYO15A c.7184_7185delTT variant is predicted to result in premature protein termination (p.Phe2395*). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/451626/). Nonsense variants in MYO15A are expected to be pathogenic. This variant is interpreted as pathogenic. -

Rare genetic deafness Pathogenic:1

Sep 18, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Phe2395X variant in MYO15A has been previously reported by our laboratory in 1 individual with hearing loss who was compound heterozygous for a second lik ely pathogenic MYO15A variant. This variant has also been identified in 0.002% ( 2/111718) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however this frequency is low enough to be consistent with a recessive carrier f requency. This nonsense variant leads to a premature termination codon at positi on 2395, which is predicted to lead to a truncated or absent protein. Loss of MY O15A function is an established disease mechanism for autosomal recessive nonsyn dromic hearing loss. In summary, the p.Phe2395X variant meets criteria to be cla ssified as pathogenic for hearing loss in an autosomal recessive manner. ACMG/AM P Criteria applied: PVS1, PM2, PM3. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1415858976; hg19: chr17-18052864;