chr17-18120214-T-A

Position:

• chr17-18120214-T-A

Variant summary

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

The NM_016239.4(MYO15A):​c.1414T>A​(p.Ser472Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.24

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=0.16152847).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.1414T>A	p.Ser472Thr	missense_variant	2/66	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.1414T>A	p.Ser472Thr	missense_variant	2/66		NM_016239.4	ENSP00000495481	P1
MYO15A	ENST00000583079.1	n.1047T>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000161 AC: 4 AN: 248104 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134964

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

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: 0.00000411 AC: 6 AN: 1460492 Hom.: 0 Cov.: 36 AF XY: 0.00000413 AC XY: 3 AN XY: 726514

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000134

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.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 10, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 25, 2016

The p.Ser472Thr variant in MYO15A has now been identified by our laboratory in t wo individuals with hearing loss, but a variant affecting the second copy of the MYO15A gene was not identified in either of them. It has not been identified in large population studies. Computational prediction tools and conservation analy sis do not provide strong support for or against an impact to the protein. In su mmary, the clinical significance of the p.Ser472Thr variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.026	T;T;T
Eigen	Benign	0.14
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.61	T;.;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	.;L;L
MutationTaster	Benign	0.72	N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.1	.;N;.
REVEL	Benign	0.074
Sift	Benign	0.11	.;T;.
Sift4G	Uncertain	0.0020	D;D;.
Polyphen		0.80	.;P;P
Vest4		0.29
MutPred		0.26		Loss of phosphorylation at S472 (P = 0.0821);Loss of phosphorylation at S472 (P = 0.0821);Loss of phosphorylation at S472 (P = 0.0821);
MVP		0.44
ClinPred		0.17	T
GERP RS		4.3
Varity_R		0.13
gMVP		0.62

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: rs886042317; hg19: chr17-18023528;