chr12-80708053-G-T

Position:

chr12-80708053-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP4BS2

The ENST00000228641.4(MYF6):c.334G>T(p.Ala112Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,614,160 control chromosomes in the GnomAD database, including 2 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 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 2 hom. )

Consequence

MYF6
ENST00000228641.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 9.60

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 -4 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PrimateAI, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.33798712).

BS2

High AC in GnomAd4 at 183 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYF6	NM_002469.3 linkuse as main transcript	c.334G>T	p.Ala112Ser	missense_variant	1/3	ENST00000228641.4	NP_002460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYF6	ENST00000228641.4 linkuse as main transcript	c.334G>T	p.Ala112Ser	missense_variant	1/3	1	NM_002469.3	ENSP00000228641	P1

Frequencies

GnomAD3 genomes

AF:

0.00120

AC:

183

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00175

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00112

AC:

281

AN:

251072

Hom.:

AF XY:

0.00105

AC XY:

142

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.00166

Gnomad NFE exome

AF:

0.00158

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00151

AC:

2214

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

1073

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.00114

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000591

Gnomad4 FIN exome

AF:

0.00183

Gnomad4 NFE exome

AF:

0.00174

Gnomad4 OTH exome

AF:

0.00109

GnomAD4 genome

AF:

0.00120

AC:

183

AN:

152276

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00203

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00122

Gnomad4 NFE

AF:

0.00175

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00153

Hom.:

Bravo

AF:

0.00104

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00114

AC:

138

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00185

EpiControl

AF:

0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal dominant centronuclear myopathy

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 24, 2023	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Dec 01, 2000	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 09, 2019	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PP3,PP5. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2020	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: 11053684, no PMID, 32528171) -

MYF6-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 03, 2023

The MYF6 c.334G>T variant is predicted to result in the amino acid substitution p.Ala112Ser. This variant has been reported in the literature in patients with myopathy and limb-girdle weakness; however, no additional functional or segregation studies have confirmed its pathogenicity (Kerst et al. 2000. PubMed ID: 11053684; Töpf A et al. 2020. PubMed ID: 32528171). This variant is reported in 0.17% of alleles in individuals of European (Finnish) descent, and in over 300 total alleles in the gnomAD database (http://gnomad.broadinstitute.org/variant/12-81101832-G-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.34

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.84

MVP

0.99

MPC

1.1

ClinPred

0.18

GERP RS

5.6

Varity_R

0.78

gMVP

0.59

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