rs771875597

Positions:

• chr11-47346629-C-G
• chr11-47346629-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_000256.3(MYBPC3):​c.924G>C​(p.Pro308=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000093 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0017 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYBPC3 NM_000256.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.00001529
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.54

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 11-47346629-C-G is Benign according to our data. Variant chr11-47346629-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1879202.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.54 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.924G>C	p.Pro308=	splice_region_variant, synonymous_variant	11/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.924G>C	p.Pro308=	splice_region_variant, synonymous_variant	11/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.924G>C	p.Pro308=	splice_region_variant, synonymous_variant	10/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.924G>C	p.Pro308=	splice_region_variant, synonymous_variant, NMD_transcript_variant	11/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes AF: 0.00 AC: 11 AN: 128992 Hom.: 0 Cov.: 30 FAILED QC

Gnomad AFR AF: 0.0000291

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00105

Gnomad SAS AF: 0.000287

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000483

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00175 AC: 1220 AN: 697806 Hom.: 0 Cov.: 31 AF XY: 0.00153 AC XY: 546 AN XY: 356828

Gnomad4 AFR exome AF: 0.00162

Gnomad4 AMR exome AF: 0.000189

Gnomad4 ASJ exome AF: 0.00102

Gnomad4 EAS exome AF: 0.000759

Gnomad4 SAS exome AF: 0.000339

Gnomad4 FIN exome AF: 0.000299

Gnomad4 NFE exome AF: 0.00220

Gnomad4 OTH exome AF: 0.00164

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000930 AC: 12 AN: 129076 Hom.: 0 Cov.: 30 AF XY: 0.0000812 AC XY: 5 AN XY: 61604

Gnomad4 AFR AF: 0.0000291

Gnomad4 AMR AF: 0.000169

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00105

Gnomad4 SAS AF: 0.000288

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000644

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

MYBPC3: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.085
DANN	Benign	0.21

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.096
SpliceAI score (max)		0.040		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: rs771875597; hg19: chr11-47368180;