rs199621031

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_016239.4(MYO15A):c.9620G>A(p.Arg3207His) variant causes a missense change. The variant allele was found at a frequency of 0.0000551 in 1,614,138 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 6.47

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-18163251-G-A is Pathogenic according to our data. Variant chr17-18163251-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228973.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=2, Pathogenic=2}.

BP4

Computational evidence support a benign effect (MetaRNN=0.08375016). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4 link	c.9620G>A	p.Arg3207His	missense_variant	Exon 59 of 66	ENST00000647165.2	NP_057323.3	Q9UKN7-1
MYO15A	XM_017024715.3 link	c.9623G>A	p.Arg3208His	missense_variant	Exon 57 of 64		XP_016880204.1
MYO15A	XM_017024714.3 link	c.9560G>A	p.Arg3187His	missense_variant	Exon 56 of 63		XP_016880203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 link	c.9620G>A	p.Arg3207His	missense_variant	Exon 59 of 66		NM_016239.4	ENSP00000495481.1		Q9UKN7-1

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

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:

0.0000441

AC:

AN:

249574

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135398

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000495

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1461824

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000263

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00242

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

Alfa

AF:

0.000121

Hom.:

Bravo

AF:

0.000672

ExAC

AF:

0.0000579

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 3

Pathogenic:2Uncertain:1

Aug 31, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg3207His variant (rs199621031) is reported in the medical literature in two individuals with nonsyndromic hearing loss, one who harbored a truncating variant on the other MYO15A allele and another who had a second missense variant in MYO15A (Bademci 2016 and Sommen 2016). This variant is reported in ClinVar (Variation ID: 228973) and is found in the general population with an allele frequency of 0.0036% (10/277,202 alleles) in the Genome Aggregation Database. The arginine at codon 3207 is highly conserved considering 11 species (Alamut v2.11) but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Based on the available information, the clinical significance of this variant is uncertain at this time. -

Jun 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 20, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYO15A c.9620G>A (p.Arg3207His) results in a non-conservative amino acid change located in the Band 4.1 domain (IPR019749) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 249574 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MYO15A causing Autosomal Recessive Nonsyndromic Hearing Loss 3, allowing no conclusion about variant significance. c.9620G>A has been reported in the literature in compoound heterozygous individuals affected with Autosomal Recessive Nonsyndromic Hearing Loss 3 (Bademci_2016, Sommen_2016, Yan_2017, Sloan-Heggen_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26226137, 26969326, 27068579, 27344577). ClinVar contains an entry for this variant (Variation ID: 228973). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided

Pathogenic:2

May 29, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27375115, 27068579, 26226137) -

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 3207 of the MYO15A protein (p.Arg3207His). This variant is present in population databases (rs199621031, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 26226137, 27068579; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 228973). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYO15A protein function. For these reasons, this variant has been classified as Pathogenic. -

MYO15A-related disorder

Pathogenic:1

Sep 24, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MYO15A c.9620G>A variant is predicted to result in the amino acid substitution p.Arg3207His. This variant was reported in the heterozygous state along with a likely pathogenic truncating variant in a patient with nonsyndromic hearing loss (Bademci et al. 2016. PubMed ID: 26226137) and in a second patient with hearing loss along with a second potentially causative rare missense variant (Sommen et al. 2016. PubMed ID: 27068579). At PreventionGenetics, this variant was reported in the homozygous and compound heterozygous state along with a likely pathogenic variant in two unrelated patients with hearing loss (internal data). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic. -

Rare genetic deafness

Pathogenic:1

Jan 03, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg3207His variant in MYO15A has been reported in 7 individuals with hearing loss (two homozygous, four compound heterozygous with a second likely pathogenic variant, and one compound heterozygous with another variant of uncertain significance) (Bademci 2016, Sommen 2016, LMM data). This variant has been identified in 0.01% (5/35374) Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive hearing loss. ACMG/AMP criteria applied: PM3_Strong, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.090

T;D;D;.;.;.

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.96

D;.;D;D;D;D

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.084

T;T;T;T;T;T

MetaSVM

Pathogenic

0.88

MutationAssessor

Benign

1.8

.;L;L;.;.;.

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-4.5

.;D;.;.;.;.

REVEL

Uncertain

0.60

Sift

Benign

0.042

.;D;.;.;.;.

Sift4G

Pathogenic

0.0010

D;D;.;D;.;D

Polyphen

0.94

.;P;P;.;.;.

Vest4

0.49

MVP

0.92

ClinPred

0.89

GERP RS

5.3

Varity_R

0.25

gMVP

0.52

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