rs11570076

Variant names:

• chr11-47343571-G-A
• rs11570076
• NM_000256.3:c.1144C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-47343571-G-A
• chr11-47343571-G-C
• chr11-47343571-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000256.3(MYBPC3):​c.1144C>T​(p.Arg382Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00251 in 1,611,812 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R382Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (52 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (53 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 3.64
• Publications: 12 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 (MetaRNN=0.010368973).
• BP6: Variant 11-47343571-G-A is Benign according to our data. Variant chr11-47343571-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 42506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.013 (1974/151844) while in subpopulation AFR AF = 0.045 (1863/41388). AF 95% confidence interval is 0.0433. There are 52 homozygotes in GnomAd4. There are 936 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 52 AR,AD gene

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.1144C>T	p.Arg382Trp	missense	Exon 13 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.1144C>T	p.Arg382Trp	missense	Exon 13 of 35	ENSP00000442795.1	Q14896-1
	MYBPC3	ENST00000399249.6	TSL:5	c.1144C>T	p.Arg382Trp	missense	Exon 12 of 34	ENSP00000382193.2	A8MXZ9
	MYBPC3	ENST00000544791.1	TSL:5	n.1144C>T		non_coding_transcript_exon	Exon 13 of 27	ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1964 AN: 151726 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.0449

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00466

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0130

GnomAD2 exomes AF: 0.00303 AC: 746 AN: 246538 AF XY: 0.00240

Gnomad AFR exome AF: 0.0438

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000896

Gnomad OTH exome AF: 0.00267

GnomAD4 exome AF: 0.00142 AC: 2075 AN: 1459968 Hom.: 53 Cov.: 46 AF XY: 0.00119 AC XY: 862 AN XY: 726156

African (AFR) AF: 0.0495 AC: 1656 AN: 33444

American (AMR) AF: 0.00195 AC: 87 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.000233 AC: 20 AN: 85918

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53144

Middle Eastern (MID) AF: 0.00209 AC: 12 AN: 5754

European-Non Finnish (NFE) AF: 0.0000828 AC: 92 AN: 1111130

Other (OTH) AF: 0.00343 AC: 207 AN: 60274

GnomAD4 genome AF: 0.0130 AC: 1974 AN: 151844 Hom.: 52 Cov.: 32 AF XY: 0.0126 AC XY: 936 AN XY: 74252

African (AFR) AF: 0.0450 AC: 1863 AN: 41388

American (AMR) AF: 0.00466 AC: 71 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.000624 AC: 3 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10526

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67950

Other (OTH) AF: 0.0128 AC: 27 AN: 2102

Alfa AF: 0.00441 Hom.: 53

Bravo AF: 0.0146

ESP6500AA AF: 0.0314 AC: 126

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00368 AC: 445

Asia WGS AF: 0.00231 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Hypertrophic cardiomyopathy (4)
-	-	2	Hypertrophic cardiomyopathy 4 (2)
-	-	2	not provided (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 1 (1)
-	-	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	Uncertain	0.34
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		3.6
PrimateAI	Uncertain	0.48	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Benign	0.27
Sift	Uncertain	0.0080	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.57
MVP		0.86
MPC		0.84
ClinPred		0.037	T
GERP RS		4.1
Varity_R		0.51
gMVP		0.56
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11570076; hg19: chr11-47365122; COSMIC: COSV104563690;