rs2642531

chr1-203174597-G-Cchr1-203174597-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004997.3(MYBPH):c.341C>G(p.Ala114Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,594,978 control chromosomes in the GnomAD database, including 24,005 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.24 (6106 hom., cov: 32)
  • Exomes 𝑓: 0.14 (17899 hom.)
• Consequence: MYBPH NM_004997.3 missense, splice_region
• Scores: Splicing: ADA: 0.0005832
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.31

Genes affected

MYBPH (HGNC:7552): (myosin binding protein H) Predicted to be a structural constituent of muscle. Predicted to be involved in regulation of striated muscle contraction. Predicted to be located in myosin filament. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.9930472E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.473 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPH	NM_004997.3	c.341C>G	p.Ala114Gly	missense_variant, splice_region_variant	3/11	ENST00000255416.9
MYBPH	XM_047421205.1	c.464C>G	p.Ala155Gly	missense_variant, splice_region_variant	4/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPH	ENST00000255416.9	c.341C>G	p.Ala114Gly	missense_variant, splice_region_variant	3/11	1	NM_004997.3	P1

Frequencies

GnomAD3 genomes AF: 0.237 AC: 36050 AN: 152028 Hom.: 6093 Cov.: 32

Gnomad AFR AF: 0.478

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.223

GnomAD3 exomes AF: 0.171 AC: 41278 AN: 241992 Hom.: 4569 AF XY: 0.160 AC XY: 20968 AN XY: 131118

Gnomad AFR exome AF: 0.496

Gnomad AMR exome AF: 0.236

Gnomad ASJ exome AF: 0.202

Gnomad EAS exome AF: 0.149

Gnomad SAS exome AF: 0.131

Gnomad FIN exome AF: 0.116

Gnomad NFE exome AF: 0.126

Gnomad OTH exome AF: 0.169

GnomAD4 exome AF: 0.142 AC: 205586 AN: 1442832 Hom.: 17899 Cov.: 32 AF XY: 0.140 AC XY: 100354 AN XY: 714630

Gnomad4 AFR exome AF: 0.508

Gnomad4 AMR exome AF: 0.239

Gnomad4 ASJ exome AF: 0.196

Gnomad4 EAS exome AF: 0.175

Gnomad4 SAS exome AF: 0.128

Gnomad4 FIN exome AF: 0.116

Gnomad4 NFE exome AF: 0.126

Gnomad4 OTH exome AF: 0.171

GnomAD4 genome AF: 0.237 AC: 36102 AN: 152146 Hom.: 6106 Cov.: 32 AF XY: 0.234 AC XY: 17434 AN XY: 74396

Gnomad4 AFR AF: 0.478

Gnomad4 AMR AF: 0.256

Gnomad4 ASJ AF: 0.200

Gnomad4 EAS AF: 0.148

Gnomad4 SAS AF: 0.125

Gnomad4 FIN AF: 0.113

Gnomad4 NFE AF: 0.126

Gnomad4 OTH AF: 0.220

Alfa AF: 0.149 Hom.: 1591

Bravo AF: 0.262

TwinsUK AF: 0.126 AC: 467

ALSPAC AF: 0.139 AC: 534

ESP6500AA AF: 0.486 AC: 2143

ESP6500EA AF: 0.131 AC: 1124

ExAC AF: 0.170 AC: 20623

Asia WGS AF: 0.187 AC: 649 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	17
Dann	Uncertain	0.98
DEOGEN2	Benign	0.025	T;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.13	T;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.00030	T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	0.23	P
PrimateAI	Benign	0.42	T
Sift4G	Uncertain	0.029	D;D
Polyphen		0.048	.;B
Vest4		0.053
MPC		0.14
ClinPred		0.020	T
GERP RS		4.6
Varity_R		0.13
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00058
dbscSNV1_RF	Benign	0.042
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

Other links and lift over

dbSNP: rs2642531; hg19: chr1-203143725; COSMIC: COSV55138164; COSMIC: COSV55138164;