11-47335108-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a domain Fibronectin type-III 2 (size 95) in uniprot entity MYPC3_HUMAN there are 23 pathogenic changes around while only 7 benign (77%) in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3462751).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2839C>A	p.His947Asn	missense_variant	Exon 27 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2839C>A	p.His947Asn	missense_variant	Exon 27 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2839C>A	p.His947Asn	missense_variant	Exon 26 of 34	5		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 v4.3

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;T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.0	L;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.6	N;.;N
REVEL	Benign	0.050
Sift	Benign	0.18	T;.;T
Sift4G	Uncertain	0.032	D;D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs397515988; hg19: chr11-47356659;