rs776075902

chr11-47347652-T-Achr11-47347652-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PP3_Strong

The NM_000256.3(MYBPC3):c.850A>T(p.Ser284Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. 2/3 splice prediction tools predicting alterations to normal splicing. 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. S284G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYBPC3 NM_000256.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.53

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a modified_residue Phosphoserine; by PKA and PKC (size 0) in uniprot entity MYPC3_HUMAN
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.850A>T	p.Ser284Cys	missense_variant, splice_region_variant	8/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.850A>T	p.Ser284Cys	missense_variant, splice_region_variant	8/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.850A>T	p.Ser284Cys	missense_variant, splice_region_variant	8/34	5		A2
MYBPC3	ENST00000544791.1	c.850A>T	p.Ser284Cys	missense_variant, splice_region_variant, NMD_transcript_variant	8/27	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1421994 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 703480

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 03, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. An algorithm developed specifically for the MYBPC3 gene suggests that this missense change is likely to be tolerated (PMID: 21310275). ClinVar contains an entry for this variant (Variation ID: 566285). This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 284 of the MYBPC3 protein (p.Ser284Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
CardioboostCm	Benign	0.014
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Benign	0.33	T;T;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.72	T;T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.0	M;.;.
MutationTaster	Benign	0.83	N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.092
Sift	Uncertain	0.023	D;D;D
Sift4G	Uncertain	0.047	D;D;D
Polyphen		0.87	P;.;.
Vest4		0.43
MutPred		0.40		Loss of phosphorylation at S284 (P = 0.0037);Loss of phosphorylation at S284 (P = 0.0037);Loss of phosphorylation at S284 (P = 0.0037);
MVP		0.89
MPC		0.42
ClinPred		0.91	D
GERP RS		4.5
Varity_R		0.23
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.36		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: rs776075902; hg19: chr11-47369203;