17-18142232-C-T

Position:

• chr17-18142232-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016239.4(MYO15A):​c.5803C>T​(p.Arg1935Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.42

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3845887).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.5803C>T	p.Arg1935Trp	missense_variant	24/66	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.5803C>T	p.Arg1935Trp	missense_variant	24/66		NM_016239.4	ENSP00000495481	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 248402 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 134936

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460692 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726644

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000826 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.039	T;T;T
Eigen	Benign	0.066
Eigen_PC	Benign	0.011
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T;.;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	.;L;L
MutationTaster	Benign	0.75	D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.3	.;D;.
REVEL	Benign	0.23
Sift	Benign	0.068	.;T;.
Sift4G	Uncertain	0.022	D;D;.
Polyphen		1.0	.;D;D
Vest4		0.69
MutPred		0.64		Loss of disorder (P = 0.0014);Loss of disorder (P = 0.0014);Loss of disorder (P = 0.0014);
MVP		0.45
ClinPred		0.45	T
GERP RS		-0.37
Varity_R		0.16
gMVP		0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs200041829; hg19: chr17-18045546;