rs886038623

Variant names:

• chr17-18120654-C-T
• rs886038623
• NM_016239.4:c.1854C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_016239.4(MYO15A):​c.1854C>T​(p.Asp618Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000347 in 1,439,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: MYO15A NM_016239.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.62
• 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 17-18120654-C-T is Benign according to our data. Variant chr17-18120654-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 260699.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.62 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016239.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	NM_016239.4	MANE Select	c.1854C>T	p.Asp618Asp	synonymous	Exon 2 of 66	NP_057323.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.1854C>T	p.Asp618Asp	synonymous	Exon 2 of 66	ENSP00000495481.1
	MYO15A	ENST00000583079.1	TSL:6	n.1487C>T		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000347 AC: 5 AN: 1439100 Hom.: 0 Cov.: 49 AF XY: 0.00000420 AC XY: 3 AN XY: 715036

African (AFR) AF: 0.00 AC: 0 AN: 33048

American (AMR) AF: 0.00 AC: 0 AN: 43292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25722

East Asian (EAS) AF: 0.00 AC: 0 AN: 38928

South Asian (SAS) AF: 0.00 AC: 0 AN: 84022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43850

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5410

European-Non Finnish (NFE) AF: 0.00000452 AC: 5 AN: 1105242

Other (OTH) AF: 0.00 AC: 0 AN: 59586

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	7.0
DANN	Benign	0.75
PhyloP100		1.6

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: rs886038623; hg19: chr17-18023968;