rs755653624

Variant summary

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

The NM_000256.3(MYBPC3):​c.3284C>T​(p.Thr1095Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000107 in 1,588,640 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T1095T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

4
9
7

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 5.96
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYBPC3NM_000256.3 linkuse as main transcriptc.3284C>T p.Thr1095Met missense_variant 30/35 ENST00000545968.6 NP_000247.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYBPC3ENST00000545968.6 linkuse as main transcriptc.3284C>T p.Thr1095Met missense_variant 30/355 NM_000256.3 ENSP00000442795 P4Q14896-1
MYBPC3ENST00000399249.6 linkuse as main transcriptc.3284C>T p.Thr1095Met missense_variant 29/345 ENSP00000382193 A2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152128
Hom.:
0
Cov.:
33
show subpopulations
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
GnomAD3 exomes
AF:
0.0000242
AC:
5
AN:
206520
Hom.:
0
AF XY:
0.0000269
AC XY:
3
AN XY:
111338
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000654
Gnomad SAS exome
AF:
0.0000769
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000222
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000111
AC:
16
AN:
1436512
Hom.:
0
Cov.:
34
AF XY:
0.0000140
AC XY:
10
AN XY:
712146
show subpopulations
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:
0.0000729
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000819
Gnomad4 OTH exome
AF:
0.0000168
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152128
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74298
show subpopulations
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
ExAC
AF:
0.0000249
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 02, 2023This missense variant replaces threonine with methionine at codon 1095 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 32841044, 33148509; Furqan 2015, dissertation, Careggi University). This variant has been identified in 5/206520 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioSep 04, 2019- -
not provided Uncertain:2
Uncertain significance, no assertion criteria providedprovider interpretationStanford Center for Inherited Cardiovascular Disease, Stanford UniversitySep 08, 2016- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 08, 2017A variant of uncertain significance has been identified in the MYBPC3 gene. The T1095M variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T1095M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is only conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. -
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 23, 2022This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1095 of the MYBPC3 protein (p.Thr1095Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 30297972). ClinVar contains an entry for this variant (Variation ID: 407315). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthMay 14, 2024This missense variant replaces threonine with methionine at codon 1095 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two related individuals affected with hypertrophic cardiomyopathy (Furqan, 2015). This variant has also been identified in 5/206520 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Hypertrophic cardiomyopathy 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMolecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart InstituteFeb 03, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.38
CardioboostCm
Benign
0.0060
BayesDel_addAF
Benign
-0.063
T
BayesDel_noAF
Benign
-0.33
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.36
T;T;T
Eigen
Pathogenic
0.74
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.95
D;D;D
M_CAP
Pathogenic
0.44
D
MetaRNN
Uncertain
0.61
D;D;D
MetaSVM
Uncertain
-0.21
T
MutationAssessor
Uncertain
2.6
M;.;.
MutationTaster
Benign
0.96
D;D;D
PrimateAI
Benign
0.47
T
PROVEAN
Uncertain
-2.4
N;.;N
REVEL
Benign
0.21
Sift
Uncertain
0.0060
D;.;D
Sift4G
Uncertain
0.0070
D;D;D
Vest4
0.33
MVP
0.91
MPC
0.83
ClinPred
0.67
D
GERP RS
5.4
Varity_R
0.20
gMVP
0.55

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: rs755653624; hg19: chr11-47354791; API