11-47335108-G-T

Variant names:

• chr11-47335108-G-T
• rs397515988
• NM_000256.3:c.2839C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000256.3(MYBPC3):​c.2839C>A​(p.His947Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H947Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.947
• Publications: 1 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3462751).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	NM_000256.3	MANE Select	c.2839C>A	p.His947Asn	missense	Exon 27 of 35	NP_000247.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	ENST00000545968.6	TSL:5 MANE Select	c.2839C>A	p.His947Asn	missense	Exon 27 of 35	ENSP00000442795.1
	MYBPC3	ENST00000399249.6	TSL:5	c.2839C>A	p.His947Asn	missense	Exon 26 of 34	ENSP00000382193.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 30, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The His947Asn variant has not been reported in the literature nor detected in is olation in our laboratory. Histidine (His) at position 947 is not 100% conserve d across different species (chicken and frog have isoleucine and zebrafish has a tyrosine), reducing the likelihood that the change is pathogenic. In summary, the clinical significance of this variant cannot be determined at this time.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
CardioboostCm	Benign	0.0099
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.95
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.050
Sift	Benign	0.18	T
Sift4G	Uncertain	0.032	D
Vest4		0.45
MVP		0.79
MPC		0.48
ClinPred		0.47	T
GERP RS		4.4
Varity_R		0.20
gMVP		0.60
Mutation Taster		=95/5	polymorphism

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: rs397515988; hg19: chr11-47356659;