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rs730880569

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate

The NM_000256.3(MYBPC3):​c.2543C>T​(p.Ala848Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A848E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

11
8
1

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.60
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 uncertain in NM_000256.3
PP3
MetaRNN computational evidence supports a deleterious effect, 0.91

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MYBPC3NM_000256.3 linkuse as main transcriptc.2543C>T p.Ala848Val missense_variant 25/35 ENST00000545968.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MYBPC3ENST00000545968.6 linkuse as main transcriptc.2543C>T p.Ala848Val missense_variant 25/355 NM_000256.3 P4Q14896-1
MYBPC3ENST00000399249.6 linkuse as main transcriptc.2543C>T p.Ala848Val missense_variant 24/345 A2
MYBPC3ENST00000544791.1 linkuse as main transcriptc.*48C>T 3_prime_UTR_variant, NMD_transcript_variant 25/275

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000808
AC:
2
AN:
247484
Hom.:
0
AF XY:
0.00000745
AC XY:
1
AN XY:
134280
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000556
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1460764
Hom.:
0
Cov.:
33
AF XY:
0.00000413
AC XY:
3
AN XY:
726660
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
ExAC
AF:
0.00000825
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsAug 03, 2021- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsOct 13, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.90
CardioboostCm
Uncertain
0.10
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Pathogenic
0.31
CADD
Uncertain
26
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.44
T;T;T
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.99
D;D;D
M_CAP
Pathogenic
0.59
D
MetaRNN
Pathogenic
0.91
D;D;D
MetaSVM
Uncertain
0.62
D
MutationAssessor
Pathogenic
4.4
H;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.68
T
PROVEAN
Uncertain
-3.6
D;.;D
REVEL
Pathogenic
0.78
Sift
Uncertain
0.0010
D;.;D
Sift4G
Uncertain
0.0020
D;D;D
Vest4
0.88
MVP
0.92
MPC
0.83
ClinPred
0.99
D
GERP RS
4.6
Varity_R
0.88
gMVP
0.90

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs730880569; hg19: chr11-47359001; API