chr17-18171676-G-A

Position:

chr17-18171676-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_016239.4(MYO15A):c.10121G>A(p.Arg3374His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000731 in 1,613,784 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00028 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.529

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.012215823).

BP6

Variant 17-18171676-G-A is Benign according to our data. Variant chr17-18171676-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227629.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr17-18171676-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MYO15A	NM_016239.4 linkuse as main transcript	c.10121G>A	p.Arg3374His	missense_variant	63/66	ENST00000647165.2	NP_057323.3
MYO15A	XM_017024715.3 linkuse as main transcript	c.10124G>A	p.Arg3375His	missense_variant	61/64		XP_016880204.1
MYO15A	XM_017024714.3 linkuse as main transcript	c.10061G>A	p.Arg3354His	missense_variant	60/63		XP_016880203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 linkuse as main transcript	c.10121G>A	p.Arg3374His	missense_variant	63/66		NM_016239.4	ENSP00000495481	P1	Q9UKN7-1

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000917

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000137

AC:

AN:

249024

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135232

show subpopulations

Gnomad AFR exome

AF:

0.00110

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000513

AC:

AN:

1461522

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.000806

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000336

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000282

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.000914

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000191

Hom.:

Bravo

AF:

0.000253

ESP6500AA

AF:

0.00147

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000149

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 11, 2015

p.Arg3374His in exon 63 of MYO15A: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. O f note, >10 mammals have a histidine (His) at this position despite high nearby amino acid sequence conservation. In addition, computational prediction tools d o not suggest a high likelihood of impact to the protein. It has been identified in 0.13% (12/9514) of African chromosomes by the Exome Aggregation Consortium ( ExAC, http://exac.broadinstitute.org; dbSNP rs201794696). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.46

CADD

Benign

3.7

DANN

Benign

0.80

DEOGEN2

Benign

0.034

T;T;T;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.083

LIST_S2

Benign

0.68

T;.;T;T;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.012

T;T;T;T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

0.35

.;N;N;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.20

PROVEAN

Benign

-2.0

.;N;.;.;.

REVEL

Benign

0.23

Sift

Benign

0.35

.;T;.;.;.

Sift4G

Benign

0.23

T;T;.;T;.

Polyphen

0.0040

.;B;B;.;.

Vest4

0.17

MVP

0.25

ClinPred

0.0041

GERP RS

-5.0

Varity_R

0.042

gMVP

0.095

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

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