rs751006503

chr17-18158580-C-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.9025C>T(p.Pro3009Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,614,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.807

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=0.09629455).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.9025C>T	p.Pro3009Ser	missense_variant	52/66	ENST00000647165.2
MYO15A	XM_017024715.3	c.9028C>T	p.Pro3010Ser	missense_variant	50/64
MYO15A	XM_017024714.3	c.8965C>T	p.Pro2989Ser	missense_variant	49/63

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.9025C>T	p.Pro3009Ser	missense_variant	52/66		NM_016239.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249500 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135384

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461854 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

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: 0.00000450

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74492

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.00000827 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 28, 2015

Variant classified as Uncertain Significance - Favor Benign. The p.Pro3009Ser va riant in MYO15A has not been previously reported in individuals with hearing los s, but has been identified in 1/11572 Latino chromosomes by the Exome Aggregatio n Consortium (ExAC, http://exac.broadinstitute.org). Although this variant has b een seen in the general population, its frequency is not high enough to rule out a pathogenic role. The proline (Pro) at position 3009 is not conserved in mamma ls or evolutionarily distant species with 2 mammals (prairie vole and guinea pig ) having a serine (Ser) at this position, suggesting that the variant may be tol erated. Additional computational prediction tools do not provide strong support for or against an impact to the protein. In summary, the clinical significance o f this variant cannot be determined with certainty; however, the conservation da ta suggests that it is more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	13
Dann	Benign	0.78
DEOGEN2	Benign	0.033	T;T;T;.;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.57	T;.;T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.096	T;T;T;T;T
MetaSVM	Benign	-0.65	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.39	T
Sift4G	Benign	0.065	T;T;.;T;.
Polyphen		0.0050	.;B;B;.;.
Vest4		0.21
MutPred		0.20		Loss of catalytic residue at P3008 (P = 0.0131);Loss of catalytic residue at P3008 (P = 0.0131);Loss of catalytic residue at P3008 (P = 0.0131);.;.;
MVP		0.52
ClinPred		0.11	T
GERP RS		2.7
Varity_R		0.045
gMVP		0.40

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: rs751006503; hg19: chr17-18061894;