17-18173861-T-C

Variant names:

• chr17-18173861-T-C
• rs854800
• NM_016239.4:c.10431T>C

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.10431T>C​(p.Tyr3477Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.745 in 1,613,820 control chromosomes in the GnomAD database, including 450,805 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (46714 hom., cov: 34)
  • Exomes 𝑓: 0.74 (404091 hom.)
• Consequence: MYO15A NM_016239.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.791
• Publications: 26 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

ENSG00000266677 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 17-18173861-T-C is Benign according to our data. Variant chr17-18173861-T-C is described in ClinVar as Benign. ClinVar VariationId is 45744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.867 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.10431T>C	p.Tyr3477Tyr	synonymous	Exon 65 of 66	NP_057323.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.10431T>C	p.Tyr3477Tyr	synonymous	Exon 65 of 66	ENSP00000495481.1	Q9UKN7-1
	MYO15A	ENST00000433411.7	TSL:1	n.1957T>C		non_coding_transcript_exon	Exon 12 of 13
	MYO15A	ENST00000578575.1	TSL:1	n.*531+1571T>C		intron	N/A	ENSP00000466630.1	K7EMS7

Frequencies

GnomAD3 genomes AF: 0.779 AC: 118554 AN: 152146 Hom.: 46649 Cov.: 34

Gnomad AFR AF: 0.874

Gnomad AMI AF: 0.657

Gnomad AMR AF: 0.775

Gnomad ASJ AF: 0.802

Gnomad EAS AF: 0.641

Gnomad SAS AF: 0.586

Gnomad FIN AF: 0.747

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.753

Gnomad OTH AF: 0.773

GnomAD2 exomes AF: 0.734 AC: 181585 AN: 247468 AF XY: 0.724

Gnomad AFR exome AF: 0.871

Gnomad AMR exome AF: 0.784

Gnomad ASJ exome AF: 0.809

Gnomad EAS exome AF: 0.639

Gnomad FIN exome AF: 0.749

Gnomad NFE exome AF: 0.746

Gnomad OTH exome AF: 0.753

GnomAD4 exome AF: 0.742 AC: 1083874 AN: 1461556 Hom.: 404091 Cov.: 71 AF XY: 0.736 AC XY: 535235 AN XY: 727092

African (AFR) AF: 0.878 AC: 29405 AN: 33480

American (AMR) AF: 0.783 AC: 34994 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.808 AC: 21124 AN: 26136

East Asian (EAS) AF: 0.643 AC: 25523 AN: 39700

South Asian (SAS) AF: 0.589 AC: 50800 AN: 86258

European-Finnish (FIN) AF: 0.752 AC: 39954 AN: 53110

Middle Eastern (MID) AF: 0.766 AC: 4416 AN: 5768

European-Non Finnish (NFE) AF: 0.748 AC: 832325 AN: 1111994

Other (OTH) AF: 0.751 AC: 45333 AN: 60392

GnomAD4 genome AF: 0.779 AC: 118680 AN: 152264 Hom.: 46714 Cov.: 34 AF XY: 0.775 AC XY: 57671 AN XY: 74438

African (AFR) AF: 0.874 AC: 36333 AN: 41568

American (AMR) AF: 0.775 AC: 11860 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.802 AC: 2784 AN: 3470

East Asian (EAS) AF: 0.641 AC: 3316 AN: 5172

South Asian (SAS) AF: 0.586 AC: 2831 AN: 4834

European-Finnish (FIN) AF: 0.747 AC: 7909 AN: 10592

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.753 AC: 51192 AN: 68016

Other (OTH) AF: 0.772 AC: 1631 AN: 2114

Alfa AF: 0.761 Hom.: 119180

Bravo AF: 0.787

Asia WGS AF: 0.607 AC: 2113 AN: 3478

EpiCase AF: 0.733

EpiControl AF: 0.734

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Autosomal recessive nonsyndromic hearing loss 3 (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.10
DANN	Benign	0.52
PhyloP100		-0.79
Mutation Taster		=95/5	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: rs854800; hg19: chr17-18077175; COSMIC: COSV52753907; COSMIC: COSV52753907;