17-18148133-C-T

Position:

chr17-18148133-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The NM_016239.4(MYO15A):c.6614C>T(p.Thr2205Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00441 in 1,613,862 control chromosomes in the GnomAD database, including 28 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 0.0040 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0044 ( 26 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.57

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:

MYO15A (HGNC:):

MYO15A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM1

In a domain MyTH4 1 (size 152) in uniprot entity MYO15_HUMAN there are 8 pathogenic changes around while only 2 benign (80%) in NM_016239.4

BP4

Computational evidence support a benign effect (MetaRNN=0.011911124).

BP6

Variant 17-18148133-C-T is Benign according to our data. Variant chr17-18148133-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 6956.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=4}. Variant chr17-18148133-C-T is described in Lovd as [Likely_benign].

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 linkuse as main transcript	c.6614C>T	p.Thr2205Ile	missense_variant	31/66	ENST00000647165.2	NP_057323.3	Q9UKN7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 linkuse as main transcript	c.6614C>T	p.Thr2205Ile	missense_variant	31/66		NM_016239.4	ENSP00000495481.1		Q9UKN7-1
MYO15A	ENST00000578999.1 linkuse as main transcript	n.199C>T		non_coding_transcript_exon_variant	2/4	5

Frequencies

GnomAD3 genomes

AF:

0.00400

AC:

609

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000699

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0203

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00481

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00430

AC:

1072

AN:

249018

Hom.:

AF XY:

0.00429

AC XY:

581

AN XY:

135276

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00177

Gnomad FIN exome

AF:

0.0194

Gnomad NFE exome

AF:

0.00471

Gnomad OTH exome

AF:

0.00462

GnomAD4 exome

AF:

0.00445

AC:

6503

AN:

1461510

Hom.:

Cov.:

AF XY:

0.00439

AC XY:

3189

AN XY:

727064

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.00123

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00181

Gnomad4 FIN exome

AF:

0.0178

Gnomad4 NFE exome

AF:

0.00455

Gnomad4 OTH exome

AF:

0.00434

GnomAD4 genome

AF:

0.00400

AC:

609

AN:

152352

Hom.:

Cov.:

AF XY:

0.00432

AC XY:

322

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000697

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.0203

Gnomad4 NFE

AF:

0.00481

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00580

Hom.:

Bravo

AF:

0.00244

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.000494

AC:

ESP6500EA

AF:

0.00395

AC:

ExAC

AF:

0.00417

AC:

504

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00409

EpiControl

AF:

0.00480

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 23, 2019	This variant is associated with the following publications: (PMID: 30245029, 11735029, 17546645, 12545186, 23208854, 26308726, 27375115, 30579064) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	MYO15A: BS2 -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 19, 2012	Thr2205Ile variant in exon 31 of MYO15A: This variant is not expected to have cl inical significance because it has been identified in has been reported in 0.4% (33/8348) of European American chromosomes chromosomes from a broad population b y the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP r s121908970). It has been reported in the hemizygous state in an individual with Smith-Lemli-Opitz sydnrome (Liburd 2001) and homozygous in one individual with hearing loss who also carries a homozygous nonsense variant in MYO15A (Nal 2007) ; however, these reports are likely due to the frequency of this variant and not a reflection of its role in hearing loss. -

Deafness, with smith-magenis syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2001

- -

Autosomal recessive nonsyndromic hearing loss 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Nonsyndromic genetic hearing loss

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Jan 05, 2024

Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as Likely benign. Following criteria are met: BS1 - BS1: Allele frequency is greater than expected for disorder PP3 - PP3: Computational evidence support a deleterious effect on the gene or gene product (REVEL >=0.644 & <0.932 OR SpliceAI >0.50) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.050

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;D;D

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.64

T;.;T

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Uncertain

0.74

MutationAssessor

Pathogenic

2.9

.;M;M

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-4.3

.;D;.

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0020

.;D;.

Sift4G

Uncertain

0.0020

D;D;.

Polyphen

0.99

.;D;D

Vest4

0.54

MVP

0.89

ClinPred

0.045

GERP RS

3.1

Varity_R

0.29

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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