rs8077577

Variant names:

• chr17-18161416-C-T
• rs8077577
• NM_016239.4:c.9486C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_016239.4(MYO15A):​c.9486C>T​(p.Asp3162Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 1,613,840 control chromosomes in the GnomAD database, including 29,024 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene MYO15A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.19 (2857 hom., cov: 33)
  • Exomes 𝑓: 0.18 (26167 hom.)
• Consequence: MYO15A NM_016239.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.83
• Publications: 16 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)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for MYO15A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 17-18161416-C-T is Benign according to our data. Variant chr17-18161416-C-T is described in ClinVar as Benign. ClinVar VariationId is 45774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

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.9486C>T	p.Asp3162Asp	synonymous	Exon 57 of 66	NP_057323.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.9486C>T	p.Asp3162Asp	synonymous	Exon 57 of 66	ENSP00000495481.1	Q9UKN7-1
	MYO15A	ENST00000433411.7	TSL:1	n.936C>T		non_coding_transcript_exon	Exon 4 of 13
	MYO15A	ENST00000473013.1	TSL:1	n.670C>T		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28706 AN: 152020 Hom.: 2844 Cov.: 33

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.242

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.209

GnomAD2 exomes AF: 0.170 AC: 42355 AN: 249316 AF XY: 0.176

Gnomad AFR exome AF: 0.212

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.237

Gnomad EAS exome AF: 0.00679

Gnomad FIN exome AF: 0.144

Gnomad NFE exome AF: 0.205

Gnomad OTH exome AF: 0.193

GnomAD4 exome AF: 0.184 AC: 269367 AN: 1461702 Hom.: 26167 Cov.: 33 AF XY: 0.186 AC XY: 134930 AN XY: 727168

African (AFR) AF: 0.220 AC: 7370 AN: 33480

American (AMR) AF: 0.113 AC: 5063 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 6349 AN: 26136

East Asian (EAS) AF: 0.00461 AC: 183 AN: 39700

South Asian (SAS) AF: 0.186 AC: 16064 AN: 86256

European-Finnish (FIN) AF: 0.143 AC: 7618 AN: 53278

Middle Eastern (MID) AF: 0.305 AC: 1757 AN: 5766

European-Non Finnish (NFE) AF: 0.192 AC: 213576 AN: 1111970

Other (OTH) AF: 0.189 AC: 11387 AN: 60392

GnomAD4 genome AF: 0.189 AC: 28767 AN: 152138 Hom.: 2857 Cov.: 33 AF XY: 0.184 AC XY: 13670 AN XY: 74378

African (AFR) AF: 0.211 AC: 8760 AN: 41506

American (AMR) AF: 0.163 AC: 2490 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 839 AN: 3470

East Asian (EAS) AF: 0.0108 AC: 56 AN: 5168

South Asian (SAS) AF: 0.172 AC: 827 AN: 4818

European-Finnish (FIN) AF: 0.146 AC: 1550 AN: 10586

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.200 AC: 13588 AN: 67988

Other (OTH) AF: 0.212 AC: 447 AN: 2110

Alfa AF: 0.196 Hom.: 6344

Bravo AF: 0.193

Asia WGS AF: 0.108 AC: 375 AN: 3478

EpiCase AF: 0.209

EpiControl AF: 0.218

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Autosomal recessive nonsyndromic hearing loss 3 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.62
DANN	Benign	0.80
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs8077577; hg19: chr17-18064730; COSMIC: COSV52758423; COSMIC: COSV52758423;