NM_000256.3:c.927-9G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3PP5_Very_Strong

The NM_000256.3(MYBPC3):c.927-9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000121 in 1,568,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000208256: Published functional studies demonstrated that c.927-9 G>A leads to skipping of exon 12 and results in either an abnormal truncated protein or haploinsufficiency due to the creation of an unstable transcript (Helms et al., 2014" and additional evidence is available in ClinVar. The gene MYBPC3 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 intron

Scores

Splicing: ADA: 0.9636

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:19

Conservation

PhyloP100: 0.355

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hypertrophic cardiomyopathy 4
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
left ventricular noncompaction 10
Inheritance: AD, AR Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
atrial fibrillation
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
congenital heart disease
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
dilated cardiomyopathy
Inheritance: AR, AD Classification: LIMITED Submitted by: ClinGen

MYBPC3 links:

Genome browser will be placed here

ACMG classification

Specifications for MYBPC3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000208256: Published functional studies demonstrated that c.927-9 G>A leads to skipping of exon 12 and results in either an abnormal truncated protein or haploinsufficiency due to the creation of an unstable transcript (Helms et al., 2014; Crehalet et al., 2012); SCV000280287: Both in silico and in vitro data suggest that this variant causes aberrant splicing (Crehalet, 2012).; SCV000696335: The variant allele was found at a frequency of 5.4e-06 in 186306 control chromosomes. c.927-9G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Rodriguez-Garcia_2010, Crehalet_2012, Das_2014), and co-segregated with disease in multiple families (Rodriguez-Garcia_2010, Das_2014). These data indicate that the variant is very likely to be associated with disease. no; SCV000059334: "In vitro splicing studies suggest that it disrupts splicing, leading to an abnormal or absent protein" (Crehalet 2012, Helms 2014 PMID: 25031304).; SCV000546426: Studies have shown that this variant results in inclusion of intron 11, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 25031304).; SCV004814327: A mini-gene splicing assay exhibited the existence of a short transcript lacking exon 12 in approximately equal amount of the normal transcript in wild type Hela cells (Crehalet 2012, doi.org/10.4081/cardiogenetics.2012.e6).; SCV000840018: Studies characterizing the effect of the c.927-9G>A variant on MYBPC3 function have shown splicing at exon 11 is absent and protein levels are reduced (PMID: 25031304).; SCV006581373: Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 25031304).; SCV001358526: A mini-gene splicing assay has shown that the wild type construct results in approximately equal amounts of the normal transcript and the short transcript lacking exon 12, suggesting that the weak acceptor site of intron 11 was not always recognized (Crehalet 2012, doi.org/10.4081/cardiogenetics.2012.e6). This study has also shown that this variant causes complete skipping of exon 12, which is expected to result in frameshift and premature translation stop. PMID: 25031304

PP5

Variant 11-47346379-C-T is Pathogenic according to our data. Variant chr11-47346379-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 42807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000256.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	NM_000256.3	MANE Select	c.927-9G>A		intron	N/A	NP_000247.2	Q14896-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MYBPC3	ENST00000545968.6	TSL:5 MANE Select	c.927-9G>A	intron	N/A	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6	TSL:5	c.927-9G>A	intron	N/A	ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1	TSL:5	n.927-9G>A	intron	N/A	ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000538

AC:

AN:

185906

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000136

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000113

AC:

AN:

1415840

Hom.:

Cov.:

AF XY:

0.00000715

AC XY:

AN XY:

699326

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32702

American (AMR)

AF:

0.00

AC:

AN:

39340

Ashkenazi Jewish (ASJ)

AF:

0.0000415

AC:

AN:

24086

East Asian (EAS)

AF:

0.00

AC:

AN:

38072

South Asian (SAS)

AF:

0.00

AC:

AN:

79514

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50798

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5536

European-Non Finnish (NFE)

AF:

0.0000129

AC:

AN:

1087168

Other (OTH)

AF:

0.0000171

AC:

AN:

58624

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000427

Hom.:

Bravo

AF:

0.0000151

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypertrophic cardiomyopathy 4 (5)

not provided (5)

Hypertrophic cardiomyopathy (4)

Cardiomyopathy (2)

Primary familial hypertrophic cardiomyopathy (2)

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Benign

0.75

PhyloP100

0.35

Mutation Taster

=24/76

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.96

Splicevardb

3.0

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.28

Position offset: -9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over