NM_000256.3:c.501C>T

Variant names:

• chr11-47350018-G-A
• rs397516054
• NM_000256.3:c.501C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000256.3(MYBPC3):​c.501C>T​(p.Thr167Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,559,156 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: -0.498
• Publications: 2 publications found

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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AR, AD 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
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 11-47350018-G-A is Benign according to our data. Variant chr11-47350018-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 42761.
• BP7: Synonymous conserved (PhyloP=-0.498 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	NM_000256.3	MANE Select	c.501C>T	p.Thr167Thr	synonymous	Exon 4 of 35	NP_000247.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	ENST00000545968.6	TSL:5 MANE Select	c.501C>T	p.Thr167Thr	synonymous	Exon 4 of 35	ENSP00000442795.1
	MYBPC3	ENST00000399249.6	TSL:5	c.501C>T	p.Thr167Thr	synonymous	Exon 4 of 34	ENSP00000382193.2
	MYBPC3	ENST00000544791.1	TSL:5	n.501C>T		non_coding_transcript_exon	Exon 4 of 27	ENSP00000444259.1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 151406 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000124 AC: 21 AN: 168882 AF XY: 0.000155

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000771

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000252

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000204

Gnomad OTH exome AF: 0.000216

GnomAD4 exome AF: 0.000143 AC: 201 AN: 1407750 Hom.: 0 Cov.: 37 AF XY: 0.000145 AC XY: 101 AN XY: 695376

African (AFR) AF: 0.00 AC: 0 AN: 31974

American (AMR) AF: 0.0000813 AC: 3 AN: 36886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25264

East Asian (EAS) AF: 0.000138 AC: 5 AN: 36298

South Asian (SAS) AF: 0.0000501 AC: 4 AN: 79810

European-Finnish (FIN) AF: 0.0000202 AC: 1 AN: 49614

Middle Eastern (MID) AF: 0.000353 AC: 2 AN: 5660

European-Non Finnish (NFE) AF: 0.000165 AC: 179 AN: 1083934

Other (OTH) AF: 0.000120 AC: 7 AN: 58310

GnomAD4 genome AF: 0.000125 AC: 19 AN: 151406 Hom.: 0 Cov.: 33 AF XY: 0.0000946 AC XY: 7 AN XY: 73994

African (AFR) AF: 0.00 AC: 0 AN: 41320

American (AMR) AF: 0.000197 AC: 3 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5116

South Asian (SAS) AF: 0.00 AC: 0 AN: 4752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67864

Other (OTH) AF: 0.000480 AC: 1 AN: 2082

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.0000907

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	1	-	Hypertrophic cardiomyopathy 4 (1)
-	-	1	Left ventricular noncompaction 10 (1)
-	-	1	MYBPC3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.43
DANN	Benign	0.87
PhyloP100		-0.50
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: 6

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

Other links and lift over

dbSNP: rs397516054; hg19: chr11-47371569;