rs1001523088

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2PP5_ModerateBP4

The NM_016239.4(MYO15A):c.6893G>A(p.Arg2298Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000687 in 1,455,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.22

Publications

3 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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-18148889-G-A is Pathogenic according to our data. Variant chr17-18148889-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 517648.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.24490309). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MYO15A	NM_016239.4 link	c.6893G>A	p.Arg2298Gln	missense_variant	Exon 33 of 66	ENST00000647165.2	NP_057323.3
MYO15A	XM_017024715.3 link	c.6896G>A	p.Arg2299Gln	missense_variant	Exon 31 of 64		XP_016880204.1
MYO15A	XM_017024714.3 link	c.6833G>A	p.Arg2278Gln	missense_variant	Exon 30 of 63		XP_016880203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 link	c.6893G>A	p.Arg2298Gln	missense_variant	Exon 33 of 66		NM_016239.4	ENSP00000495481.1
MYO15A	ENST00000578999.1 link	n.405G>A		non_coding_transcript_exon_variant	Exon 3 of 4	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000852

AC:

AN:

234652

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000600

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

AF:

0.00000687

AC:

AN:

1455306

Hom.:

Cov.:

AF XY:

0.00000691

AC XY:

AN XY:

723282

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33362

American (AMR)

AF:

0.0000455

AC:

AN:

43934

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25942

East Asian (EAS)

AF:

0.0000506

AC:

AN:

39490

South Asian (SAS)

AF:

0.00

AC:

AN:

84822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52730

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000361

AC:

AN:

1109134

Other (OTH)

AF:

0.0000166

AC:

AN:

60126

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Nonsyndromic genetic hearing loss

Pathogenic:1

Feb 02, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg2298Gln variant in MYO15A has been previously reported in the homozygous state in two individuals with profound sensorineural hearing loss, and segregated in 9 affected family members from two families (Sloan-Heggen 2015 PMID 26969326, personal communication with authors, Abu Rayyan 2020 PMID 32747562). In addition, the variant was identified by our laboratory in an individual with hearing loss who was compound heterozygous for p.Arg2298Gln and a likely pathogenic MYO15A variant. It has also been identified in 0.005996% (2/33356) of Latino/Admixed American chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss. ACMG/AMP Criteria applied: PP1_Strong, PM2_Supporting, PM3. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.030

T;T;T

Eigen

Benign

0.0079

Eigen_PC

Benign

0.10

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.92

D;.;D

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Benign

-0.31

MutationAssessor

Uncertain

2.6

.;M;M

PhyloP100

5.2

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.5

.;N;.

REVEL

Benign

0.28

Sift

Uncertain

0.017

.;D;.

Sift4G

Uncertain

0.0030

D;D;.

Polyphen

0.29

.;B;B

Vest4

0.24

MutPred

0.39

Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);

MVP

0.78

ClinPred

0.65

GERP RS

4.0

Varity_R

0.12

gMVP

0.65

Mutation Taster

=75/25

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over