1-203174597-G-T

Position:

• chr1-203174597-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004997.3(MYBPH):​c.341C>A​(p.Ala114Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,348 control chromosomes in the GnomAD database, with no homozygous occurrence. 16/23 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A114G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MYBPH NM_004997.3 missense, splice_region
• Scores: Splicing: ADA: 0.0003175
• 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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPH	NM_004997.3	c.341C>A	p.Ala114Asp	missense_variant, splice_region_variant	3/11	ENST00000255416.9	NP_004988.2
MYBPH	XM_047421205.1	c.464C>A	p.Ala155Asp	missense_variant, splice_region_variant	4/12		XP_047277161.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPH	ENST00000255416.9	c.341C>A	p.Ala114Asp	missense_variant, splice_region_variant	3/11	1	NM_004997.3	ENSP00000255416	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443348 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 714918

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.023	T;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.4	.;L
MutationTaster	Benign	0.15	P
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.5	.;N
REVEL	Benign	0.096
Sift	Benign	0.14	.;T
Sift4G	Benign	0.16	T;T
Polyphen		0.18	.;B
Vest4		0.31
MutPred		0.54		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP		0.67
MPC		0.25
ClinPred		0.34	T
GERP RS		4.6
Varity_R		0.19
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00032
dbscSNV1_RF	Benign	0.038
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;