17-18150840-G-C

Position:

• chr17-18150840-G-C

Variant summary

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

The NM_016239.4(MYO15A):​c.7400G>C​(p.Arg2467Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,441,758 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.81

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.7400G>C	p.Arg2467Pro	missense_variant	38/66	ENST00000647165.2	NP_057323.3
MYO15A	XM_017024715.3	c.7403G>C	p.Arg2468Pro	missense_variant	36/64		XP_016880204.1
MYO15A	XM_017024714.3	c.7340G>C	p.Arg2447Pro	missense_variant	35/63		XP_016880203.1
LOC124903944	XR_007065652.1	n.377+763C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.7400G>C	p.Arg2467Pro	missense_variant	38/66		NM_016239.4	ENSP00000495481.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1441758 Hom.: 0 Cov.: 33 AF XY: 0.00000140 AC XY: 1 AN XY: 715554

Gnomad4 AFR exome AF: 0.0000606

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.030	T;T;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.77	T;.;T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.0	.;M;M
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.5	.;N;.
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0020	.;D;.
Sift4G	Benign	0.067	T;T;.
Polyphen		1.0	.;D;D
Vest4		0.55
MutPred		0.49		Loss of MoRF binding (P = 0.0372);Loss of MoRF binding (P = 0.0372);Loss of MoRF binding (P = 0.0372);
MVP		0.86
ClinPred		0.92	D
GERP RS		4.0
Varity_R		0.47
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs865982060; hg19: chr17-18054154;