rs3729936

Variant names:

• chr11-47335865-G-A
• rs3729936
• NM_000256.3:c.2737+12C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000256.3(MYBPC3):​c.2737+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0293 in 1,466,450 control chromosomes in the GnomAD database, including 965 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (125 hom., cov: 30)
  • Exomes 𝑓: 0.029 (840 hom.)
• Consequence: MYBPC3 NM_000256.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -3.39
• Publications: 10 publications found

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]

MYBPC3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 4

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AD, AR Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy

  Inheritance: AR, AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 11-47335865-G-A is Benign according to our data. Variant chr11-47335865-G-A is described in ClinVar as Benign. ClinVar VariationId is 42653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000256.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	NM_000256.3	MANE Select	c.2737+12C>T		intron	N/A	NP_000247.2	Q14896-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	ENST00000545968.6	TSL:5 MANE Select	c.2737+12C>T		intron	N/A	ENSP00000442795.1	Q14896-1
	MYBPC3	ENST00000399249.6	TSL:5	c.2737+12C>T		intron	N/A	ENSP00000382193.2	A8MXZ9
	MYBPC3	ENST00000544791.1	TSL:5	n.*242+12C>T		intron	N/A	ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes AF: 0.0350 AC: 5315 AN: 151928 Hom.: 126 Cov.: 30

Gnomad AFR AF: 0.0529

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.0136

Gnomad EAS AF: 0.0423

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.0223

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0257

Gnomad OTH AF: 0.0345

GnomAD2 exomes AF: 0.0332 AC: 3675 AN: 110846 AF XY: 0.0379

Gnomad AFR exome AF: 0.0474

Gnomad AMR exome AF: 0.00972

Gnomad ASJ exome AF: 0.00936

Gnomad EAS exome AF: 0.0303

Gnomad FIN exome AF: 0.0220

Gnomad NFE exome AF: 0.0236

Gnomad OTH exome AF: 0.0191

GnomAD4 exome AF: 0.0286 AC: 37645 AN: 1314404 Hom.: 840 Cov.: 34 AF XY: 0.0302 AC XY: 19414 AN XY: 642274

African (AFR) AF: 0.0549 AC: 1537 AN: 27972

American (AMR) AF: 0.0121 AC: 340 AN: 28162

Ashkenazi Jewish (ASJ) AF: 0.0102 AC: 236 AN: 23118

East Asian (EAS) AF: 0.0332 AC: 1014 AN: 30500

South Asian (SAS) AF: 0.0956 AC: 6517 AN: 68170

European-Finnish (FIN) AF: 0.0199 AC: 915 AN: 45948

Middle Eastern (MID) AF: 0.0280 AC: 146 AN: 5206

European-Non Finnish (NFE) AF: 0.0244 AC: 25142 AN: 1031428

Other (OTH) AF: 0.0334 AC: 1798 AN: 53900

GnomAD4 genome AF: 0.0350 AC: 5317 AN: 152046 Hom.: 125 Cov.: 30 AF XY: 0.0359 AC XY: 2669 AN XY: 74334

African (AFR) AF: 0.0530 AC: 2196 AN: 41430

American (AMR) AF: 0.0147 AC: 224 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0136 AC: 47 AN: 3466

East Asian (EAS) AF: 0.0416 AC: 215 AN: 5170

South Asian (SAS) AF: 0.116 AC: 555 AN: 4798

European-Finnish (FIN) AF: 0.0223 AC: 236 AN: 10598

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0257 AC: 1746 AN: 67996

Other (OTH) AF: 0.0347 AC: 73 AN: 2106

Alfa AF: 0.0354 Hom.: 54

Bravo AF: 0.0329

Asia WGS AF: 0.116 AC: 404 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Hypertrophic cardiomyopathy 4 (4)
-	-	3	not provided (3)
-	-	2	Hypertrophic cardiomyopathy (2)
-	-	1	Left ventricular noncompaction 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.014
DANN	Benign	0.47
PhyloP100		-3.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3729936; hg19: chr11-47357416;