rs7940442

chr11-47343655-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000256.3(MYBPC3):c.1091-31G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00934 in 1,567,034 control chromosomes in the GnomAD database, including 1,174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (565 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (609 hom.)
• Consequence: MYBPC3 NM_000256.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.145

Genes affected

MYBPC3 (HGNC:7551): (myosin binding protein C3) MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 11-47343655-C-T is Benign according to our data. Variant chr11-47343655-C-T is described in ClinVar as [Benign]. Clinvar id is 255623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47343655-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.1091-31G>A		intron_variant		ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1091-31G>A		intron_variant		5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.1091-31G>A		intron_variant		5		A2
MYBPC3	ENST00000544791.1	c.1091-31G>A		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0473 AC: 7194 AN: 152004 Hom.: 560 Cov.: 32

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0169

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.0364

GnomAD3 exomes AF: 0.0127 AC: 2542 AN: 200394 Hom.: 192 AF XY: 0.00943 AC XY: 1027 AN XY: 108906

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.00800

Gnomad ASJ exome AF: 0.00135

Gnomad EAS exome AF: 0.0000614

Gnomad SAS exome AF: 0.000507

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000339

Gnomad OTH exome AF: 0.00621

GnomAD4 exome AF: 0.00523 AC: 7394 AN: 1414916 Hom.: 609 Cov.: 36 AF XY: 0.00444 AC XY: 3107 AN XY: 699064

Gnomad4 AFR exome AF: 0.181

Gnomad4 AMR exome AF: 0.00830

Gnomad4 ASJ exome AF: 0.000917

Gnomad4 EAS exome AF: 0.0000515

Gnomad4 SAS exome AF: 0.000563

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000237

Gnomad4 OTH exome AF: 0.0123

GnomAD4 genome AF: 0.0476 AC: 7242 AN: 152118 Hom.: 565 Cov.: 32 AF XY: 0.0460 AC XY: 3421 AN XY: 74382

Gnomad4 AFR AF: 0.165

Gnomad4 AMR AF: 0.0168

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.0360

Alfa AF: 0.0247 Hom.: 42

Bravo AF: 0.0542

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.26
Dann	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs7940442; hg19: chr11-47365206; COSMIC: COSV57026190;