rs11570115

Variant names:

• chr11-47333354-T-C
• rs11570115
• NM_000256.3:c.3191-21A>G

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.3191-21A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0945 in 1,544,986 control chromosomes in the GnomAD database, including 7,915 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.071 (542 hom., cov: 33)
  • Exomes 𝑓: 0.097 (7373 hom.)
• Consequence: MYBPC3 NM_000256.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.73
• Publications: 25 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AR, AD 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
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

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

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 11-47333354-T-C is Benign according to our data. Variant chr11-47333354-T-C is described in ClinVar as Benign. ClinVar VariationId is 188578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.3191-21A>G		intron_variant	Intron 29 of 34	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3191-21A>G		intron_variant	Intron 29 of 34	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.3191-21A>G		intron_variant	Intron 28 of 33	5		ENSP00000382193.2

Frequencies

GnomAD3 genomes AF: 0.0715 AC: 10878 AN: 152042 Hom.: 542 Cov.: 33

Gnomad AFR AF: 0.0177

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.0582

Gnomad ASJ AF: 0.0805

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0307

Gnomad FIN AF: 0.0947

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.0903

GnomAD2 exomes AF: 0.0705 AC: 11837 AN: 167790 AF XY: 0.0708

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.0441

Gnomad ASJ exome AF: 0.0870

Gnomad EAS exome AF: 0.000380

Gnomad FIN exome AF: 0.0869

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.0737

GnomAD4 exome AF: 0.0970 AC: 135069 AN: 1392826 Hom.: 7373 Cov.: 34 AF XY: 0.0950 AC XY: 65105 AN XY: 685160

African (AFR) AF: 0.0141 AC: 453 AN: 32046

American (AMR) AF: 0.0448 AC: 1661 AN: 37110

Ashkenazi Jewish (ASJ) AF: 0.0832 AC: 1967 AN: 23642

East Asian (EAS) AF: 0.000162 AC: 6 AN: 37020

South Asian (SAS) AF: 0.0302 AC: 2366 AN: 78380

European-Finnish (FIN) AF: 0.0907 AC: 4401 AN: 48536

Middle Eastern (MID) AF: 0.0598 AC: 333 AN: 5568

European-Non Finnish (NFE) AF: 0.111 AC: 119077 AN: 1072986

Other (OTH) AF: 0.0835 AC: 4805 AN: 57538

GnomAD4 genome AF: 0.0715 AC: 10873 AN: 152160 Hom.: 542 Cov.: 33 AF XY: 0.0686 AC XY: 5103 AN XY: 74382

African (AFR) AF: 0.0176 AC: 733 AN: 41534

American (AMR) AF: 0.0580 AC: 888 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0805 AC: 279 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.0309 AC: 149 AN: 4824

European-Finnish (FIN) AF: 0.0947 AC: 1003 AN: 10596

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7511 AN: 67960

Other (OTH) AF: 0.0894 AC: 189 AN: 2114

Alfa AF: 0.0974 Hom.: 683

Bravo AF: 0.0668

Asia WGS AF: 0.0150 AC: 52 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.17
DANN	Benign	0.30
PhyloP100		-1.7
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs11570115; hg19: chr11-47354905; COSMIC: COSV57034284; COSMIC: COSV57034284;