Variant rs190471225 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002469.3(MYF6):c.184G>A(p.Val62Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000372 in 1,614,162 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 0 hom. )

Consequence

MYF6
NM_002469.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.52

Variant links:

Genes affected

MYF6 (HGNC:7566): (myogenic factor 6) The protein encoded by this gene is a probable basic helix-loop-helix (bHLH) DNA binding protein involved in muscle differentiation. The encoded protein likely acts as a heterodimer with another bHLH protein. Defects in this gene are a cause of autosomal dominant centronuclear myopathy (ADCNM). [provided by RefSeq, May 2010]

MYF6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15628883).

BS2

High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYF6	NM_002469.3 linkuse as main transcript	c.184G>A	p.Val62Ile	missense_variant	1/3	ENST00000228641.4	NP_002460.1	P23409

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYF6	ENST00000228641.4 linkuse as main transcript	c.184G>A	p.Val62Ile	missense_variant	1/3	1	NM_002469.3	ENSP00000228641.3		P23409

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000368

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000247

AC:

AN:

251318

Hom.:

AF XY:

0.000272

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000520

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:

0.000370

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000391

AC:

572

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000366

AC XY:

266

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

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:

0.0000187

Gnomad4 NFE exome

AF:

0.000477

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000190

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000385

Hom.:

Bravo

AF:

0.000234

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000313

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 09, 2024

Variant summary: MYF6 c.184G>A (p.Val62Ile) results in a conservative amino acid change located in the Myogenic muscle-specific protein, N-terminal domain (IPR002546) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 251318 control chromosomes (gnomAD). c.184G>A has been reported in the literature in an individual affected with Miyoshi myopathy without strong evidence of causality (Scalco_2017). This report does not provide unequivocal conclusions about association of the variant with MYF6-Related Disorders. Co-occurrence with another pathogenic variant was reported in this patient (DYSF c.3203_3204del, p.Leu1068fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28053302). ClinVar contains an entry for this variant (Variation ID: 472751). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Autosomal dominant centronuclear myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 62 of the MYF6 protein (p.Val62Ile). This variant is present in population databases (rs190471225, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MYF6-related conditions. ClinVar contains an entry for this variant (Variation ID: 472751). 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 not expected to disrupt MYF6 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Dec 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.035

MetaRNN

Benign

0.16

MetaSVM

Uncertain

0.22

MutationAssessor

Uncertain

2.2

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.59

REVEL

Uncertain

0.34

Sift

Uncertain

0.013

Sift4G

Benign

0.19

Polyphen

1.0

Vest4

0.45

MVP

0.99

MPC

1.0

ClinPred

0.12

GERP RS

5.6

Varity_R

0.32

gMVP

0.20

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