rs1555543296

Positions:

• chr17-18135775-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_016239.4(MYO15A):​c.4547T>G​(p.Leu1516Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L1516L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.04

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 17-18135775-T-G is Pathogenic according to our data. Variant chr17-18135775-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520966.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.4547T>G	p.Leu1516Arg	missense_variant	13/66	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.4547T>G	p.Leu1516Arg	missense_variant	13/66		NM_016239.4	ENSP00000495481	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 25, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T;D;D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.86	D;.;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	.;H;H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.0	.;D;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	.;D;D
Vest4		0.88
MutPred		0.90		Gain of disorder (P = 0.0525);Gain of disorder (P = 0.0525);Gain of disorder (P = 0.0525);
MVP		0.97
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.95
gMVP		0.87

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: rs1555543296; hg19: chr17-18039089;