rs727504945

chr11-47351247-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP4_Strong BP6

The NM_000256.3(MYBPC3):c.284T>C(p.Ile95Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000577 in 1,387,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I95L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.278

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 Likely_benign. Variant got -3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000256.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.047510028).
• BP6: Variant 11-47351247-A-G is Benign according to our data. Variant chr11-47351247-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179554.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.284T>C	p.Ile95Thr	missense_variant	2/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.284T>C	p.Ile95Thr	missense_variant	2/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.284T>C	p.Ile95Thr	missense_variant	2/34	5		A2
MYBPC3	ENST00000544791.1	c.284T>C	p.Ile95Thr	missense_variant, NMD_transcript_variant	2/27	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000594 AC: 1 AN: 168306 Hom.: 0 AF XY: 0.0000112 AC XY: 1 AN XY: 89668

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: 0.0000146

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000577 AC: 8 AN: 1387372 Hom.: 0 Cov.: 37 AF XY: 0.00000735 AC XY: 5 AN XY: 680386

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000273

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: 0.00000562

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 17, 2017

A variant of uncertain significance has been identified in the MYBPC3 gene. The I95T variant has not been published as pathogenic or been reported as benign to our knowledge. Additionally, this variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The I95T 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 not conserved across species and threonine (T) is the wild-type residue at this position in multiple mammalian species. Furthermore, in silico analysis predicts this variant likely does not alter the protein structure/function. Finally, there are conflicting classifications in ClinVar where this variant is classified as both a variant of uncertain significance and a likely benign variant by other clinical laboratories (ClinVar SCV000206064.3, SCV000219630.2; Landrum et al., 2016). -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 25, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 95 of the MYBPC3 protein (p.Ile95Thr). 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 variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 179554). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 02, 2014

Ile95Thr in exon 2 of MYBPC3: This variant is not expected to have clinical sign ificance due to a lack of conservation across species, including mammals. Of not e, >10 mammals have a threonine (Thr) at this position despite high nearby amino acid conservation. In addition, this variant was predicted to be benign using a computational tool clinically validated by our laboratory. This tool's benign p rediction is estimated to be correct 89% of the time (Jordan 2011). Ile95Thr in exon 2 of MYBPC3 (allele frequency = n/a) -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
CardioboostCm	Benign	0.0024
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	7.3
Dann	Benign	0.40
DEOGEN2	Benign	0.11	T;T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.64	T;T;T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.048	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.57	N;N;N
REVEL	Benign	0.022
Sift	Benign	0.32	T;T;T
Sift4G	Benign	0.72	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.044
MutPred		0.37		Gain of disorder (P = 0.0432);Gain of disorder (P = 0.0432);Gain of disorder (P = 0.0432);
MVP		0.14
MPC		0.28
ClinPred		0.048	T
GERP RS		-6.7
Varity_R		0.065
gMVP		0.23

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: rs727504945; hg19: chr11-47372798;