rs861278

Variant names:

• chr17-18156180-C-T
• rs861278
• NM_016239.4:c.8460-15C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016239.4(MYO15A):​c.8460-15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,613,590 control chromosomes in the GnomAD database, including 124,731 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9348 hom., cov: 32)
  • Exomes 𝑓: 0.39 (115383 hom.)
• Consequence: MYO15A NM_016239.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.402
• Publications: 5 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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-18156180-C-T is Benign according to our data. Variant chr17-18156180-C-T is described in ClinVar as Benign. ClinVar VariationId is 45769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.413 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.8460-15C>T		intron	N/A	NP_057323.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.8460-15C>T		intron	N/A	ENSP00000495481.1	Q9UKN7-1
	MYO15A	ENST00000418233.7	TSL:2	c.252-15C>T		intron	N/A	ENSP00000408800.3	Q9UKN7-2
	MYO15A	ENST00000644795.1		c.252-15C>T		intron	N/A	ENSP00000495720.1	A0A2R8Y712

Frequencies

GnomAD3 genomes AF: 0.336 AC: 51026 AN: 151988 Hom.: 9346 Cov.: 32

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.0869

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.422

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.417

Gnomad OTH AF: 0.329

GnomAD2 exomes AF: 0.334 AC: 83017 AN: 248462 AF XY: 0.334

Gnomad AFR exome AF: 0.223

Gnomad AMR exome AF: 0.276

Gnomad ASJ exome AF: 0.408

Gnomad EAS exome AF: 0.0908

Gnomad FIN exome AF: 0.437

Gnomad NFE exome AF: 0.411

Gnomad OTH exome AF: 0.367

GnomAD4 exome AF: 0.388 AC: 567652 AN: 1461482 Hom.: 115383 Cov.: 50 AF XY: 0.383 AC XY: 278553 AN XY: 727044

African (AFR) AF: 0.227 AC: 7581 AN: 33470

American (AMR) AF: 0.279 AC: 12458 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 10456 AN: 26124

East Asian (EAS) AF: 0.101 AC: 4004 AN: 39698

South Asian (SAS) AF: 0.215 AC: 18522 AN: 86240

European-Finnish (FIN) AF: 0.438 AC: 23390 AN: 53392

Middle Eastern (MID) AF: 0.309 AC: 1773 AN: 5746

European-Non Finnish (NFE) AF: 0.421 AC: 467568 AN: 1111734

Other (OTH) AF: 0.363 AC: 21900 AN: 60372

GnomAD4 genome AF: 0.336 AC: 51039 AN: 152108 Hom.: 9348 Cov.: 32 AF XY: 0.330 AC XY: 24508 AN XY: 74364

African (AFR) AF: 0.232 AC: 9619 AN: 41472

American (AMR) AF: 0.298 AC: 4553 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 1373 AN: 3470

East Asian (EAS) AF: 0.0875 AC: 453 AN: 5176

South Asian (SAS) AF: 0.212 AC: 1022 AN: 4820

European-Finnish (FIN) AF: 0.422 AC: 4465 AN: 10592

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.417 AC: 28370 AN: 67966

Other (OTH) AF: 0.325 AC: 686 AN: 2110

Alfa AF: 0.385 Hom.: 2166

Bravo AF: 0.320

Asia WGS AF: 0.162 AC: 565 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	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	-0.80
CADD	Benign	3.8
DANN	Benign	0.68
PhyloP100		-0.40
Mutation Taster		=100/0	polymorphism (auto)

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: rs861278; hg19: chr17-18059494; COSMIC: COSV52754137; COSMIC: COSV52754137;