rs200583193

Variant names:

• chr17-18157744-C-T
• rs200583193
• NM_016239.4:c.8811C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-18157744-C-T
• chr17-18157744-C-G

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.8811C>T​(p.His2937His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00231 in 1,606,396 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene MYO15A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (8 hom.)
• Consequence: MYO15A NM_016239.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -3.02
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 17-18157744-C-T is Benign according to our data. Variant chr17-18157744-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 164558.
• BP7: Synonymous conserved (PhyloP=-3.02 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00183 (279/152354) while in subpopulation NFE AF = 0.00298 (203/68026). AF 95% confidence interval is 0.00265. There are 1 homozygotes in GnomAd4. There are 139 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 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.8811C>T	p.His2937His	synonymous	Exon 51 of 66	NP_057323.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.8811C>T	p.His2937His	synonymous	Exon 51 of 66	ENSP00000495481.1	Q9UKN7-1
	MYO15A	ENST00000418233.7	TSL:2	c.603C>T	p.His201His	synonymous	Exon 9 of 24	ENSP00000408800.3	Q9UKN7-2
	MYO15A	ENST00000644795.1		c.603C>T	p.His201His	synonymous	Exon 9 of 23	ENSP00000495720.1	A0A2R8Y712

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 279 AN: 152236 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00298

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00190 AC: 454 AN: 239492 AF XY: 0.00199

Gnomad AFR exome AF: 0.000132

Gnomad AMR exome AF: 0.000668

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00163

Gnomad NFE exome AF: 0.00322

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.00236 AC: 3437 AN: 1454042 Hom.: 8 Cov.: 33 AF XY: 0.00236 AC XY: 1710 AN XY: 723722

African (AFR) AF: 0.000359 AC: 12 AN: 33466

American (AMR) AF: 0.000492 AC: 22 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00195 AC: 168 AN: 86252

European-Finnish (FIN) AF: 0.00161 AC: 74 AN: 45856

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.00275 AC: 3058 AN: 1111842

Other (OTH) AF: 0.00162 AC: 98 AN: 60324

GnomAD4 genome AF: 0.00183 AC: 279 AN: 152354 Hom.: 1 Cov.: 33 AF XY: 0.00187 AC XY: 139 AN XY: 74502

African (AFR) AF: 0.000577 AC: 24 AN: 41586

American (AMR) AF: 0.00163 AC: 25 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00298 AC: 203 AN: 68026

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00247 Hom.: 0

Bravo AF: 0.00159

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00219

ClinVar

ClinVar submissions

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)
-	-	1	MYO15A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.47
DANN	Benign	0.61
PhyloP100		-3.0
Mutation Taster		=99/1	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: rs200583193; hg19: chr17-18061058;