rs2955379

Positions:

• chr17-18149553-T-A
• chr17-18149553-T-C
• chr17-18149553-T-G

Variant summary

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

The NM_016239.4(MYO15A):​c.7185T>A​(p.Phe2395Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F2395F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.603

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]

LOC124903944 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.7185T>A	p.Phe2395Leu	missense_variant	35/66	ENST00000647165.2	NP_057323.3
MYO15A	XM_017024715.3	c.7188T>A	p.Phe2396Leu	missense_variant	33/64		XP_016880204.1
MYO15A	XM_017024714.3	c.7125T>A	p.Phe2375Leu	missense_variant	32/63		XP_016880203.1
LOC124903944	XR_007065652.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.7185T>A	p.Phe2395Leu	missense_variant	35/66		NM_016239.4	ENSP00000495481	P1
MYO15A	ENST00000578999.1	n.806T>A		non_coding_transcript_exon_variant	4/4	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 69

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;D;D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.82	T;.;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.72	D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.2	.;M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.1	.;D;.
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0020	.;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		0.99	.;D;D
Vest4		0.53
MutPred		0.65		Gain of disorder (P = 0.0695);Gain of disorder (P = 0.0695);Gain of disorder (P = 0.0695);
MVP		0.78
ClinPred		0.96	D
GERP RS		-1.2
Varity_R		0.40
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2955379; hg19: chr17-18052867;