17-18119715-C-T

Variant names:

• chr17-18119715-C-T
• rs200695102
• NM_016239.4:c.915C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_016239.4(MYO15A):​c.915C>T​(p.Tyr305Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000777 in 1,611,586 control chromosomes in the GnomAD database, including 11 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 0.00058 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00080 (9 hom.)
• Consequence: MYO15A NM_016239.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.422
• Publications: 3 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 17-18119715-C-T is Benign according to our data. Variant chr17-18119715-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 226792.
• BP7: Synonymous conserved (PhyloP=-0.422 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000798 (1165/1459384) while in subpopulation SAS AF = 0.00539 (465/86258). AF 95% confidence interval is 0.00499. There are 9 homozygotes in GnomAdExome4. There are 681 alleles in the male GnomAdExome4 subpopulation. Median coverage is 36. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	NM_016239.4	MANE Select	c.915C>T	p.Tyr305Tyr	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.915C>T	p.Tyr305Tyr	synonymous	Exon 2 of 66	ENSP00000495481.1
	MYO15A	ENST00000583079.1	TSL:6	n.548C>T		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.000579 AC: 88 AN: 152084 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00123 AC: 301 AN: 245544 AF XY: 0.00147

Gnomad AFR exome AF: 0.0000673

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00550

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000295

Gnomad NFE exome AF: 0.000574

Gnomad OTH exome AF: 0.000666

GnomAD4 exome AF: 0.000798 AC: 1165 AN: 1459384 Hom.: 9 Cov.: 36 AF XY: 0.000938 AC XY: 681 AN XY: 726128

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00486 AC: 127 AN: 26134

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

South Asian (SAS) AF: 0.00539 AC: 465 AN: 86258

European-Finnish (FIN) AF: 0.000216 AC: 11 AN: 50966

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.000445 AC: 495 AN: 1111986

Other (OTH) AF: 0.000861 AC: 52 AN: 60372

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152202 Hom.: 2 Cov.: 33 AF XY: 0.000565 AC XY: 42 AN XY: 74394

African (AFR) AF: 0.0000482 AC: 2 AN: 41532

American (AMR) AF: 0.000196 AC: 3 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4826

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 67992

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000851 Hom.: 0

Bravo AF: 0.000484

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.4
DANN	Benign	0.88
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism

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: rs200695102; hg19: chr17-18023029; COSMIC: COSV52757851;