rs397516079

Positions:

chr11-47347036-C-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000256.3(MYBPC3):c.906-7G>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000389 in 809,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00001428

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: -1.30

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 11-47347036-C-A is Benign according to our data. Variant chr11-47347036-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42800.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Benign=1, Uncertain_significance=1}. Variant chr11-47347036-C-A is described in Lovd as [Benign]. Variant chr11-47347036-C-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.906-7G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.906-7G>T	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	5	NM_000256.3	ENSP00000442795	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.906-389G>T	intron_variant	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.906-7G>T	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant	5		ENSP00000444259

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000677

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000282

AC:

AN:

230196

Hom.:

AF XY:

0.000268

AC XY:

AN XY:

126638

show subpopulations

Gnomad AFR exome

AF:

0.0000690

Gnomad AMR exome

AF:

0.0000878

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000179

Gnomad NFE exome

AF:

0.000534

Gnomad OTH exome

AF:

0.000347

GnomAD4 exome

AF:

0.000400

AC:

263

AN:

657402

Hom.:

Cov.:

AF XY:

0.000398

AC XY:

142

AN XY:

356494

show subpopulations

Gnomad4 AFR exome

AF:

0.000108

Gnomad4 AMR exome

AF:

0.0000916

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000181

Gnomad4 NFE exome

AF:

0.000615

Gnomad4 OTH exome

AF:

0.000290

GnomAD4 genome

AF:

0.000342

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000677

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000610

Hom.:

Bravo

AF:

0.000242

EpiCase

AF:

0.000545

EpiControl

AF:

0.000712

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 10, 2022	Variant summary: MYBPC3 c.906-7G>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. In a mini gene assay, the variant was reported to have no impact on splicing (Frisso_2016). The variant allele was found at a frequency of 0.00028 in 230196 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MYBPC3 causing Hypertrophic Cardiomyopathy (0.00028 vs 0.001), allowing no conclusion about variant significance. c.906-7G>T has been reported in the literature in at least one individual affected with Hypertrophic Cardiomyopathy, without strong evidence for causality (Frisso_2016). This report does not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Six submitters classified the variant as likely benign/benign while one classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2013	The variant is found in HCM panel(s). -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 12, 2020	The c.906-7G>T variant in MYBPC3 is classified as likely benign it has been identified in 0.06% (70/122142) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational splice prediction tools as well as in vitro RNA splicing assays do not predict and impact on splicing (Frisso 2016 PMID: 27834932). ACMG/AMP Criteria applied: BS1, BP4, BP7. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Cardiomyopathy

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 21, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 01, 2021	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2020	- -

Hypertrophic cardiomyopathy 4

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 27, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -

Hypertrophic cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

MYBPC3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 05, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.064

DANN

Benign

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000014

dbscSNV1_RF

Benign

0.028

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