rs113941605

Positions:

• chr11-47349910-G-A
• chr11-47349910-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1 BP4

The NM_000256.3(MYBPC3):​c.518C>T​(p.Thr173Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000145 in 1,453,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.64

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 Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a domain Ig-like C2-type 1 (size 103) in uniprot entity MYPC3_HUMAN there are 30 pathogenic changes around while only 10 benign (75%) in NM_000256.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.39126593).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.518C>T	p.Thr173Ile	missense_variant	5/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.518C>T	p.Thr173Ile	missense_variant	5/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.518C>T	p.Thr173Ile	missense_variant	5/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.518C>T	p.Thr173Ile	missense_variant, NMD_transcript_variant	5/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000145 AC: 21 AN: 1453226 Hom.: 0 Cov.: 31 AF XY: 0.0000152 AC XY: 11 AN XY: 722150

Gnomad4 AFR exome AF: 0.000240

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: 9.02e-7

Gnomad4 OTH exome AF: 0.000200

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 14, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 12, 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 missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 181043). 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 threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 173 of the MYBPC3 protein (p.Thr173Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
CardioboostCm	Benign	0.0024
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.58	D;T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.080
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.6	L;.;.
MutationTaster	Benign	0.58	N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Benign	0.22
Sift	Benign	0.058	T;T;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.015	B;.;.
Vest4		0.41
MutPred		0.53		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		0.86
MPC		0.25
ClinPred		0.45	T
GERP RS		2.7
Varity_R		0.19
gMVP		0.61

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

Other links and lift over

dbSNP: rs113941605; hg19: chr11-47371461;