Genetic Variant MYO15A:p.Trp1975Cys (chr17-18143580-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016239.4(MYO15A):c.5925G>T(p.Trp1975Cys) variant causes a missense 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.20

Publications

14 publications found

Variant links:

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]

MYO15A Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MYO15A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4 link	c.5925G>T	p.Trp1975Cys	missense_variant	Exon 26 of 66	ENST00000647165.2	NP_057323.3	Q9UKN7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 link	c.5925G>T	p.Trp1975Cys	missense_variant	Exon 26 of 66		NM_016239.4	ENSP00000495481.1		Q9UKN7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

167876

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1408686

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

695768

African (AFR)

AF:

0.00

AC:

AN:

32212

American (AMR)

AF:

0.00

AC:

AN:

36922

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25260

East Asian (EAS)

AF:

0.00

AC:

AN:

36780

South Asian (SAS)

AF:

0.00

AC:

AN:

80022

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49936

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5094

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1084122

Other (OTH)

AF:

0.00

AC:

AN:

58338

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000435

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 13, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Trp1975Cys variant in MYO15A has not been previously reported in individua ls with hearing loss or in large population studies. Computational prediction to ols and conservation analysis suggest that the p.Trp1975Cys variant may not impa ct the protein, though this information is not predictive enough to rule out pat hogenicity. In summary, the clinical significance of the p.Trp1975Cys variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.023

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.0076

T;T;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.61

T;.;T

M_CAP

Benign

0.054

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

0.69

.;N;N

PhyloP100

3.2

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.1

.;N;.

REVEL

Uncertain

0.32

Sift

Benign

0.18

.;T;.

Sift4G

Uncertain

0.040

D;D;.

Polyphen

0.68

.;P;P

Vest4

0.29

MutPred

0.60

Loss of MoRF binding (P = 0.0266);Loss of MoRF binding (P = 0.0266);Loss of MoRF binding (P = 0.0266);

MVP

0.88

ClinPred

0.24

GERP RS

3.3

Varity_R

0.14

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.49

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.31

Position offset: -14

DS_DG_spliceai

0.49

Position offset: -2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over