rs28928909

chr12-80708053-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3 BP4 BS2

The NM_002469.3(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 NM_002469.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 9.60

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]

ACMG classification

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 FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.33798712).
• BS2: High AC in GnomAd at 183 AD gene.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 183 AN: 152158 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.00105 AC XY: 142 AN XY: 135880

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.: 2 Cov.: 31 AF XY: 0.00148 AC XY: 1073 AN XY: 727242

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.: 0 Cov.: 32 AF XY: 0.00107 AC XY: 80 AN XY: 74464

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.: 1

Bravo AF: 0.00104

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00114 AC: 138

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal dominant centronuclear myopathy Uncertain:2 Benign:1

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

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 condition 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	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.34	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.84
MVP		0.99
MPC		1.1
ClinPred		0.18	T
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

Other links and lift over

dbSNP: rs28928909; hg19: chr12-81101832;