rs3729986

Variant names:

• chr11-47350047-C-T
• rs3729986
• NM_000256.3:c.472G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000256.3(MYBPC3):​c.472G>A​(p.Val158Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0874 in 1,563,914 control chromosomes in the GnomAD database, including 6,739 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (436 hom., cov: 33)
  • Exomes 𝑓: 0.090 (6303 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 0.742
• Publications: 46 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 -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 23 uncertain in NM_000256.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0020421147).
• BP6: Variant 11-47350047-C-T is Benign according to our data. Variant chr11-47350047-C-T is described in ClinVar as Benign. ClinVar VariationId is 42758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0981 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.472G>A	p.Val158Met	missense	Exon 4 of 35	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.472G>A	p.Val158Met	missense	Exon 4 of 35	ENSP00000442795.1	Q14896-1
	MYBPC3	ENST00000399249.6	TSL:5	c.472G>A	p.Val158Met	missense	Exon 4 of 34	ENSP00000382193.2	A8MXZ9
	MYBPC3	ENST00000544791.1	TSL:5	n.472G>A		non_coding_transcript_exon	Exon 4 of 27	ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes AF: 0.0675 AC: 10273 AN: 152132 Hom.: 436 Cov.: 33

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.0590

Gnomad ASJ AF: 0.0687

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0310

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.100

Gnomad OTH AF: 0.0621

GnomAD2 exomes AF: 0.0654 AC: 11428 AN: 174728 AF XY: 0.0651

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.0389

Gnomad ASJ exome AF: 0.0748

Gnomad EAS exome AF: 0.000321

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.0938

Gnomad OTH exome AF: 0.0718

GnomAD4 exome AF: 0.0895 AC: 126407 AN: 1411664 Hom.: 6303 Cov.: 37 AF XY: 0.0881 AC XY: 61453 AN XY: 697578

African (AFR) AF: 0.0136 AC: 438 AN: 32152

American (AMR) AF: 0.0412 AC: 1544 AN: 37520

Ashkenazi Jewish (ASJ) AF: 0.0700 AC: 1772 AN: 25318

East Asian (EAS) AF: 0.000355 AC: 13 AN: 36660

South Asian (SAS) AF: 0.0350 AC: 2800 AN: 80042

European-Finnish (FIN) AF: 0.105 AC: 5232 AN: 49994

Middle Eastern (MID) AF: 0.0676 AC: 383 AN: 5668

European-Non Finnish (NFE) AF: 0.101 AC: 109370 AN: 1085820

Other (OTH) AF: 0.0830 AC: 4855 AN: 58490

GnomAD4 genome AF: 0.0675 AC: 10273 AN: 152250 Hom.: 436 Cov.: 33 AF XY: 0.0665 AC XY: 4951 AN XY: 74458

African (AFR) AF: 0.0184 AC: 765 AN: 41570

American (AMR) AF: 0.0590 AC: 901 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0687 AC: 238 AN: 3466

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.0313 AC: 151 AN: 4832

European-Finnish (FIN) AF: 0.100 AC: 1065 AN: 10608

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.100 AC: 6803 AN: 67982

Other (OTH) AF: 0.0614 AC: 130 AN: 2116

Alfa AF: 0.0839 Hom.: 1062

Bravo AF: 0.0628

TwinsUK AF: 0.0941 AC: 349

ALSPAC AF: 0.104 AC: 401

ESP6500AA AF: 0.0171 AC: 69

ESP6500EA AF: 0.0864 AC: 718

ExAC AF: 0.0440 AC: 5121

Asia WGS AF: 0.0170 AC: 58 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Hypertrophic cardiomyopathy 4 (4)
-	-	3	Hypertrophic cardiomyopathy (3)
-	-	3	not provided (3)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Left ventricular noncompaction 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.74
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.23
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.82	P
Vest4		0.16
MPC		0.56
ClinPred		0.060	T
GERP RS		1.5
Varity_R		0.23
gMVP		0.40
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: rs3729986; hg19: chr11-47371598; COSMIC: COSV107223641;