rs3729953

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000256.3(MYBPC3):​c.2547C>T​(p.Val849Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.039 in 1,612,412 control chromosomes in the GnomAD database, including 1,639 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 121 hom., cov: 32)
Exomes 𝑓: 0.040 ( 1518 hom. )

Consequence

MYBPC3
NM_000256.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 1.32
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 Benign. Variant got -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.46).
BP6
Variant 11-47337446-G-A is Benign according to our data. Variant chr11-47337446-G-A is described in ClinVar as [Benign]. Clinvar id is 42638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47337446-G-A is described in Lovd as [Benign]. Variant chr11-47337446-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=1.33 with no splicing effect.
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYBPC3NM_000256.3 linkuse as main transcriptc.2547C>T p.Val849Val synonymous_variant 25/35 ENST00000545968.6 NP_000247.2 Q14896-1A5YM48

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYBPC3ENST00000545968.6 linkuse as main transcriptc.2547C>T p.Val849Val synonymous_variant 25/355 NM_000256.3 ENSP00000442795.1 Q14896-1
MYBPC3ENST00000399249.6 linkuse as main transcriptc.2547C>T p.Val849Val synonymous_variant 24/345 ENSP00000382193.2 A8MXZ9
MYBPC3ENST00000544791.1 linkuse as main transcriptn.*52C>T non_coding_transcript_exon_variant 25/275 ENSP00000444259.1 F5GZR4
MYBPC3ENST00000544791.1 linkuse as main transcriptn.*52C>T 3_prime_UTR_variant 25/275 ENSP00000444259.1 F5GZR4

Frequencies

GnomAD3 genomes
AF:
0.0333
AC:
5071
AN:
152214
Hom.:
123
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0208
Gnomad AMI
AF:
0.0230
Gnomad AMR
AF:
0.0160
Gnomad ASJ
AF:
0.0153
Gnomad EAS
AF:
0.0434
Gnomad SAS
AF:
0.117
Gnomad FIN
AF:
0.0465
Gnomad MID
AF:
0.0127
Gnomad NFE
AF:
0.0372
Gnomad OTH
AF:
0.0325
GnomAD3 exomes
AF:
0.0435
AC:
10737
AN:
246988
Hom.:
374
AF XY:
0.0477
AC XY:
6390
AN XY:
134046
show subpopulations
Gnomad AFR exome
AF:
0.0218
Gnomad AMR exome
AF:
0.0132
Gnomad ASJ exome
AF:
0.0124
Gnomad EAS exome
AF:
0.0379
Gnomad SAS exome
AF:
0.119
Gnomad FIN exome
AF:
0.0497
Gnomad NFE exome
AF:
0.0383
Gnomad OTH exome
AF:
0.0338
GnomAD4 exome
AF:
0.0396
AC:
57781
AN:
1460080
Hom.:
1518
Cov.:
33
AF XY:
0.0419
AC XY:
30440
AN XY:
726252
show subpopulations
Gnomad4 AFR exome
AF:
0.0219
Gnomad4 AMR exome
AF:
0.0140
Gnomad4 ASJ exome
AF:
0.0126
Gnomad4 EAS exome
AF:
0.0354
Gnomad4 SAS exome
AF:
0.111
Gnomad4 FIN exome
AF:
0.0498
Gnomad4 NFE exome
AF:
0.0359
Gnomad4 OTH exome
AF:
0.0413
GnomAD4 genome
AF:
0.0333
AC:
5069
AN:
152332
Hom.:
121
Cov.:
32
AF XY:
0.0351
AC XY:
2612
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.0210
Gnomad4 AMR
AF:
0.0159
Gnomad4 ASJ
AF:
0.0153
Gnomad4 EAS
AF:
0.0427
Gnomad4 SAS
AF:
0.116
Gnomad4 FIN
AF:
0.0465
Gnomad4 NFE
AF:
0.0372
Gnomad4 OTH
AF:
0.0326
Alfa
AF:
0.0351
Hom.:
179
Bravo
AF:
0.0281
Asia WGS
AF:
0.116
AC:
404
AN:
3478
EpiCase
AF:
0.0360
EpiControl
AF:
0.0343

ClinVar

Significance: Benign
Submissions summary: Benign:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineOct 28, 2006- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingMolecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart InstituteSep 20, 2019- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Hypertrophic cardiomyopathy 4 Benign:4
Benign, criteria provided, single submitterclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical CenterSep 21, 2015- -
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, University Medical Center UtrechtOct 10, 2014- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided Benign:2
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Left ventricular noncompaction 10 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Cardiomyopathy Benign:1
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 16, 2018- -
Hypertrophic cardiomyopathy Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsJun 16, 2015This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.46
CADD
Benign
9.3
DANN
Benign
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs3729953; hg19: chr11-47358997; API