rs727503312

Positions:

chr17-18148129-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_016239.4(MYO15A):c.6610C>T(p.Arg2204Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2204H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 1.42

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a domain MyTH4 1 (size 152) in uniprot entity MYO15_HUMAN there are 22 pathogenic changes around while only 8 benign (73%) in NM_016239.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-18148130-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1301946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.928

PP5

Variant 17-18148129-C-T is Pathogenic according to our data. Variant chr17-18148129-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 164540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4 linkuse as main transcript	c.6610C>T	p.Arg2204Cys	missense_variant	31/66	ENST00000647165.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2 linkuse as main transcript	c.6610C>T	p.Arg2204Cys	missense_variant	31/66		NM_016239.4	P1	Q9UKN7-1
MYO15A	ENST00000578999.1 linkuse as main transcript	n.195C>T		non_coding_transcript_exon_variant	2/4	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248982

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135256

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461478

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727060

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 13, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg2204 amino acid residue in MYO15A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 35062939, 35346193). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYO15A protein function. ClinVar contains an entry for this variant (Variation ID: 164540). This variant has not been reported in the literature in individuals affected with MYO15A-related conditions. This variant is present in population databases (rs727503312, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2204 of the MYO15A protein (p.Arg2204Cys). -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 31, 2017

The p.Arg2204Cys variant in MYO15A has been reported in 1 individual with conge nital severe to profound hearing loss and was determined to be in trans with ano ther pathogenic MYO15A variant. This variant has been identified in 1/111370 Eur opean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broa dinstitute.org/; dbSNP rs727503312). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessiv e carrier frequency. Computational prediction tools and conservation analyses su ggest that this variant may impact the protein, though this information is not p redictive enough to determine pathogenicity. In summary, although additional stu dies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PP4, PP3, PM2, PM3 (Richards 2015) . -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

D;D;D

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.90

D;.;D

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.93

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

.;H;H

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-7.5

.;D;.

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

.;D;.

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

1.0

.;D;D

Vest4

0.75

MutPred

0.71

Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);

MVP

0.93

ClinPred

1.0

GERP RS

4.1

Varity_R

0.69

gMVP

0.93

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over