17-18138127-C-T

Position:

chr17-18138127-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_016239.4(MYO15A):c.4888C>T(p.Arg1630Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000634 in 1,612,058 control chromosomes in the GnomAD database, including 5 homozygotes. 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 0.0026 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00043 ( 3 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 1.78

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011051863).

BP6

Variant 17-18138127-C-T is Benign according to our data. Variant chr17-18138127-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 287885.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3, Benign=3}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00263 (400/152274) while in subpopulation AFR AF= 0.00891 (370/41536). AF 95% confidence interval is 0.00816. There are 2 homozygotes in gnomad4. There are 182 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4 link	c.4888C>T	p.Arg1630Cys	missense_variant	17/66	ENST00000647165.2	NP_057323.3	Q9UKN7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 link	c.4888C>T	p.Arg1630Cys	missense_variant	17/66		NM_016239.4	ENSP00000495481.1		Q9UKN7-1
MYO15A	ENST00000646238.1 link	n.152C>T		non_coding_transcript_exon_variant	2/4

Frequencies

GnomAD3 genomes

AF:

0.00258

AC:

392

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00874

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000727

AC:

180

AN:

247752

Hom.:

AF XY:

0.000557

AC XY:

AN XY:

134624

show subpopulations

Gnomad AFR exome

AF:

0.00885

Gnomad AMR exome

AF:

0.000608

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000133

Gnomad OTH exome

AF:

0.000992

GnomAD4 exome

AF:

0.000426

AC:

622

AN:

1459784

Hom.:

Cov.:

AF XY:

0.000402

AC XY:

292

AN XY:

726322

show subpopulations

Gnomad4 AFR exome

AF:

0.0101

Gnomad4 AMR exome

AF:

0.000604

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:

0.000166

Gnomad4 OTH exome

AF:

0.000894

GnomAD4 genome

AF:

0.00263

AC:

400

AN:

152274

Hom.:

Cov.:

AF XY:

0.00244

AC XY:

182

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00891

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00108

Hom.:

Bravo

AF:

0.00294

ESP6500AA

AF:

0.00648

AC:

ESP6500EA

AF:

0.000236

AC:

ExAC

AF:

0.000793

AC:

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 22, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2020	- -

Autosomal recessive nonsyndromic hearing loss 3

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 17, 2020	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Arg1630Cys in Exon 17 of MYO15A: This variant is not expected to have clinical s ignificance because it has been identified in 0.7% (23/3496) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs138861831). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 31, 2016	- -

Childhood onset hearing loss

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

National Institute on Deafness and Communication Disorders, National Institutes of Health

Jul 08, 2021

PM1, PP3 (non REVEL) / Modifications from PMID: 30311386 for classification: The genetic causes of hearing loss have not yet been well characterized in the Yoruba population, and the information regarding variant MAF in this population is still limited, so we did not exclude any variant based on their "high" MAF. PP3 criteria was applied even if the REVEL score was below 0.7, if at least two of the pathogenicity prediction algorithms used predicted that the variant was damaging or likely damaging. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;D;D

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;.;D

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Uncertain

0.70

MutationAssessor

Pathogenic

3.8

.;H;H

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-7.0

.;D;.

REVEL

Uncertain

0.62

Sift

Pathogenic

0.0

.;D;.

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

1.0

.;D;D

Vest4

0.56

MVP

0.91

ClinPred

0.12

GERP RS

5.5

Varity_R

0.85

gMVP

0.43

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