rs1245338270

Variant names:

• chr17-18120457-CG-C
• rs1245338270
• NM_016239.4:c.1661delG

Your query was ambiguous. Multiple possible variants found:

• chr17-18120457-CG-C
• chr17-18120457-CG-CGG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_016239.4(MYO15A):​c.1661delG​(p.Gly554AlafsTer75) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYO15A NM_016239.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.53
• Publications: 0 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

ACMG classification

Our verdict: Pathogenic. The variant received 11 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 17-18120457-CG-C is Pathogenic according to our data. Variant chr17-18120457-CG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1185683.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.1661delG	p.Gly554AlafsTer75	frameshift_variant	Exon 2 of 66	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.1661delG	p.Gly554AlafsTer75	frameshift_variant	Exon 2 of 66		NM_016239.4	ENSP00000495481.1
MYO15A	ENST00000583079.1	n.1294delG		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1424834 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 706770

African (AFR) AF: 0.00 AC: 0 AN: 32724

American (AMR) AF: 0.00 AC: 0 AN: 40016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25532

East Asian (EAS) AF: 0.00 AC: 0 AN: 38060

South Asian (SAS) AF: 0.00 AC: 0 AN: 83726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5422

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096546

Other (OTH) AF: 0.00 AC: 0 AN: 58940

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 3 Pathogenic:1

-

Deafness Molecular Diagnostic Center, Chinese PLA General Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5

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

Other links and lift over

dbSNP: rs1245338270; hg19: chr17-18023771;