chr11-47349911-T-C

Variant summary

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

The NM_000256.3(MYBPC3):ā€‹c.517A>Gā€‹(p.Thr173Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000438 in 1,598,858 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T173I) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.0000068 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000041 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

7
13

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 2.78
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 0 ACMG points.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MYBPC3NM_000256.3 linkuse as main transcriptc.517A>G p.Thr173Ala missense_variant 5/35 ENST00000545968.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MYBPC3ENST00000545968.6 linkuse as main transcriptc.517A>G p.Thr173Ala missense_variant 5/355 NM_000256.3 P4Q14896-1
MYBPC3ENST00000399249.6 linkuse as main transcriptc.517A>G p.Thr173Ala missense_variant 5/345 A2
MYBPC3ENST00000544791.1 linkuse as main transcriptc.517A>G p.Thr173Ala missense_variant, NMD_transcript_variant 5/275

Frequencies

GnomAD3 genomes
AF:
0.00000685
AC:
1
AN:
146034
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000152
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000446
AC:
1
AN:
224276
Hom.:
0
AF XY:
0.00000818
AC XY:
1
AN XY:
122196
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000996
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000413
AC:
6
AN:
1452824
Hom.:
0
Cov.:
31
AF XY:
0.00000277
AC XY:
2
AN XY:
721904
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000541
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000685
AC:
1
AN:
146034
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
70936
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000152
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthOct 23, 2023This missense variant replaces threonine with alanine at codon 173 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 an individual affected with hypertrophic cardiomyopathy (PMID: 28138913) and in an individual suspected to be affected with hypertrophic cardiomyopathy (PMID: 33673806). This variant has been identified in 1/224276 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 testingLabcorp Genetics (formerly Invitae), LabcorpMar 08, 2022This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 173 of the MYBPC3 protein (p.Thr173Ala). 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: 28138913, 33673806). ClinVar contains an entry for this variant (Variation ID: 179848). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineDec 11, 2019proposed classification - variant undergoing re-assessment, contact laboratory -
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMay 12, 2023This missense variant replaces threonine with alanine at codon 173 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 an individual affected with hypertrophic cardiomyopathy (PMID: 28138913) and in an individual suspected to be affected with hypertrophic cardiomyopathy (PMID: 33673806). This variant has been identified in 1/224276 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
CardioboostCm
Benign
0.0034
BayesDel_addAF
Benign
-0.012
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
22
DANN
Uncertain
0.98
DEOGEN2
Benign
0.39
T;T;T
Eigen
Benign
-0.21
Eigen_PC
Benign
-0.16
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Benign
0.72
T;T;T
M_CAP
Uncertain
0.13
D
MetaRNN
Uncertain
0.50
D;D;D
MetaSVM
Benign
-0.65
T
MutationAssessor
Uncertain
2.3
M;.;.
MutationTaster
Benign
0.86
N;N;N
PrimateAI
Benign
0.44
T
PROVEAN
Uncertain
-2.7
D;D;D
REVEL
Benign
0.17
Sift
Uncertain
0.023
D;D;D
Sift4G
Benign
0.091
T;T;T
Polyphen
0.0070
B;.;.
Vest4
0.62
MutPred
0.44
Loss of glycosylation at T173 (P = 0.085);Loss of glycosylation at T173 (P = 0.085);Loss of glycosylation at T173 (P = 0.085);
MVP
0.85
MPC
0.23
ClinPred
0.28
T
GERP RS
0.94
Varity_R
0.23
gMVP
0.54

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs727505168; hg19: chr11-47371462; API