rs749812958

Variant names:

• chr17-18132556-A-C
• rs749812958
• NM_016239.4:c.4310A>C

Your query was ambiguous. Multiple possible variants found:

• chr17-18132556-A-C
• chr17-18132556-A-G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_016239.4(MYO15A):​c.4310A>C​(p.Tyr1437Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1437C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.22
• Publications: 2 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: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_016239.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-18132556-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 517638.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 17-18132556-A-C is Pathogenic according to our data. Variant chr17-18132556-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2719474.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.4310A>C	p.Tyr1437Ser	missense_variant	Exon 11 of 66	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.4310A>C	p.Tyr1437Ser	missense_variant	Exon 11 of 66		NM_016239.4	ENSP00000495481.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246288 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459016 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725994

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111818

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jun 20, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (rs749812958, gnomAD 0.0009%). This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 1437 of the MYO15A protein (p.Tyr1437Ser). This variant has not been reported in the literature in individuals affected with MYO15A-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYO15A protein function. This variant disrupts the p.Tyr1437 amino acid residue in MYO15A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26969326, 32279305, 35346193). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.38	T;D;D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;.;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.5	.;M;M
PhyloP100		9.2
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-8.7	.;D;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		1.0	.;D;D
Vest4		0.89
MutPred		0.87		Gain of disorder (P = 0.0345);Gain of disorder (P = 0.0345);Gain of disorder (P = 0.0345);
MVP		0.95
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.96
gMVP		0.87
Mutation Taster		=5/95	disease causing

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: rs749812958; hg19: chr17-18035870;