11-47350082-G-C

Position:

• chr11-47350082-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000256.3(MYBPC3):​c.437C>G​(p.Thr146Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.203

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 4 ACMG points.

• PM1: In a region_of_interest Disordered (size 46) in uniprot entity MYPC3_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.437C>G	p.Thr146Ser	missense_variant	4/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.437C>G	p.Thr146Ser	missense_variant	4/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.437C>G	p.Thr146Ser	missense_variant	4/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.437C>G	p.Thr146Ser	missense_variant, NMD_transcript_variant	4/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74352

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
CardioboostCm	Benign	0.0028
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.80
DANN	Benign	0.66
DEOGEN2	Benign	0.088	T;T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0048	N
LIST_S2	Benign	0.32	T;T;T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.045	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.68	N;N;N
REVEL	Benign	0.039
Sift	Benign	0.94	T;T;T
Sift4G	Benign	0.71	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.072
MutPred		0.24		Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);
MVP		0.42
MPC		0.20
ClinPred		0.086	T
GERP RS		-4.9
Varity_R		0.024
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs780458215; hg19: chr11-47371633;