rs55688805

Variant names:

• chr17-18144511-G-A
• rs55688805
• NM_016239.4:c.6192G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-18144511-G-A
• chr17-18144511-G-C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_016239.4(MYO15A):​c.6192G>A​(p.Gly2064Gly) variant causes a synonymous change. The variant allele was found at a frequency of 0.00479 in 1,613,378 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0044 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0048 (23 hom.)
• Consequence: MYO15A NM_016239.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 4.75
• Publications: 2 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: Labcorp Genetics (formerly Invitae), G2P, 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 17-18144511-G-A is Benign according to our data. Variant chr17-18144511-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178446.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00437 (665/152282) while in subpopulation NFE AF = 0.00615 (418/68018). AF 95% confidence interval is 0.00566. There are 4 homozygotes in GnomAd4. There are 378 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	NM_016239.4	MANE Select	c.6192G>A	p.Gly2064Gly	synonymous	Exon 29 of 66	NP_057323.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.6192G>A	p.Gly2064Gly	synonymous	Exon 29 of 66	ENSP00000495481.1	Q9UKN7-1

Frequencies

GnomAD3 genomes AF: 0.00437 AC: 665 AN: 152164 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0190

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00614

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00439 AC: 1093 AN: 249194 AF XY: 0.00427

Gnomad AFR exome AF: 0.000840

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0201

Gnomad NFE exome AF: 0.00542

Gnomad OTH exome AF: 0.00297

GnomAD4 exome AF: 0.00483 AC: 7056 AN: 1461096 Hom.: 23 Cov.: 32 AF XY: 0.00470 AC XY: 3418 AN XY: 726858

African (AFR) AF: 0.000478 AC: 16 AN: 33478

American (AMR) AF: 0.000492 AC: 22 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0189 AC: 994 AN: 52672

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 0.00524 AC: 5831 AN: 1111986

Other (OTH) AF: 0.00287 AC: 173 AN: 60382

GnomAD4 genome AF: 0.00437 AC: 665 AN: 152282 Hom.: 4 Cov.: 31 AF XY: 0.00508 AC XY: 378 AN XY: 74448

African (AFR) AF: 0.000722 AC: 30 AN: 41552

American (AMR) AF: 0.000457 AC: 7 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0190 AC: 202 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00615 AC: 418 AN: 68018

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00437 Hom.: 3

Bravo AF: 0.00268

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.00387

EpiControl AF: 0.00367

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	-	Autosomal recessive nonsyndromic hearing loss 3 (1)
-	-	1	MYO15A-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	8.4
DANN	Benign	0.80
PhyloP100		4.8
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs55688805; hg19: chr17-18047825; COSMIC: COSV52766467; COSMIC: COSV52766467;