rs201234482

Positions:

• chr17-18130805-A-G
• chr17-18130805-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016239.4(MYO15A):​c.4033A>G​(p.Ile1345Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1345L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: MYO15A NM_016239.4 missense, splice_region
• Scores: Splicing: ADA: 0.0003879
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.39

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21246544).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.4033A>G	p.Ile1345Val	missense_variant, splice_region_variant	8/66	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.4033A>G	p.Ile1345Val	missense_variant, splice_region_variant	8/66		NM_016239.4	ENSP00000495481	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Benign	0.89
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	0.13
Eigen_PC	Benign	0.082
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.26	.;T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	0.15	N;N
MutationTaster	Benign	1.0	D
PROVEAN	Benign	0.40	N;.
REVEL	Uncertain	0.32
Sift	Benign	0.43	T;.
Sift4G	Benign	0.20	T;.
Vest4		0.45
MutPred		0.39		Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);
MVP		0.75
ClinPred		0.12	T
GERP RS		2.7
Varity_R		0.037
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00039
dbscSNV1_RF	Benign	0.034
SpliceAI score (max)		0.62		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.62		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201234482; hg19: chr17-18034119;