Genetic Variant MYO15A:p.Arg746Ser (chr17-18121038-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016239.4(MYO15A):c.2238G>C(p.Arg746Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000736 in 1,358,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.105

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1680328).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4 link	c.2238G>C	p.Arg746Ser	missense_variant	Exon 2 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.2238G>C	p.Arg746Ser	missense_variant	Exon 2 of 66		NM_016239.4	ENSP00000495481.1		Q9UKN7-1
MYO15A	ENST00000583079.1 link	n.1871G>C		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.36e-7

AC:

AN:

1358618

Hom.:

Cov.:

AF XY:

0.00000149

AC XY:

AN XY:

670106

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28246

American (AMR)

AF:

0.00

AC:

AN:

33832

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24248

East Asian (EAS)

AF:

0.00

AC:

AN:

32786

South Asian (SAS)

AF:

0.00

AC:

AN:

76632

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4844

European-Non Finnish (NFE)

AF:

9.38e-7

AC:

AN:

1066214

Other (OTH)

AF:

0.00

AC:

AN:

56556

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.063

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.019

T;T;T

Eigen

Benign

-0.93

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.46

T;.;T

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

0.69

.;N;N

PhyloP100

0.10

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.75

.;N;.

REVEL

Benign

0.12

Sift

Uncertain

0.0080

.;D;.

Sift4G

Benign

0.081

T;T;.

Polyphen

0.29

.;B;B

Vest4

0.32

MutPred

0.36

Gain of glycosylation at R746 (P = 0.0109);Gain of glycosylation at R746 (P = 0.0109);Gain of glycosylation at R746 (P = 0.0109);

MVP

0.54

ClinPred

0.11

GERP RS

1.1

Varity_R

0.097

gMVP

0.34

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over