Variant rs780458215 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BP4_Strong

The NM_000256.3(MYBPC3):c.437C>T(p.Thr146Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000071 in 1,408,112 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 Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000071 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.203

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]

MYBPC3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM1

In a region_of_interest Disordered (size 46) in uniprot entity MYPC3_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_000256.3

BP4

Computational evidence support a benign effect (MetaRNN=0.056915224).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.437C>T	p.Thr146Ile	missense_variant	4/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.437C>T	p.Thr146Ile	missense_variant	4/35	5	NM_000256.3	ENSP00000442795	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.437C>T	p.Thr146Ile	missense_variant	4/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.437C>T	p.Thr146Ile	missense_variant, NMD_transcript_variant	4/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000298

AC:

AN:

167712

Hom.:

AF XY:

0.0000336

AC XY:

AN XY:

89280

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:

0.000215

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000710

AC:

AN:

1408112

Hom.:

Cov.:

AF XY:

0.0000101

AC XY:

AN XY:

695542

show subpopulations

Gnomad4 AFR exome

AF:

0.0000312

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000100

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000349

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	This missense variant replaces threonine with isoleucine at codon 146 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 5/167712 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 submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 29, 2022	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. 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: 918905). This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 146 of the MYBPC3 protein (p.Thr146Ile). -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jan 15, 2020

This missense variant replaces threonine with isoleucine at codon 146 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 5/167712 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

0.13

CardioboostCm

Benign

0.0029

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

7.2

DANN

Benign

0.92

DEOGEN2

Benign

0.17

T;T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0046

LIST_S2

Benign

0.52

T;T;T

M_CAP

Benign

0.0060

MetaRNN

Benign

0.057

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.64

N;N;N

REVEL

Benign

0.044

Sift

Benign

0.12

T;T;T

Sift4G

Benign

0.18

T;T;T

Polyphen

0.041

B;.;.

Vest4

0.15

MVP

0.35

MPC

0.24

ClinPred

0.093

GERP RS

-4.9

Varity_R

0.034

gMVP

0.16

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over