1-203171428-C-G

Variant names:

• chr1-203171428-C-G
• rs139911521
• NM_004997.3:c.748G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004997.3(MYBPH):​c.748G>C​(p.Val250Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. V250M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYBPH NM_004997.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.374
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06961158).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004997.3. 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
	MYBPH	NM_004997.3	MANE Select	c.748G>C	p.Val250Leu	missense	Exon 5 of 11	NP_004988.2	Q13203

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPH	ENST00000255416.9	TSL:1 MANE Select	c.748G>C	p.Val250Leu	missense	Exon 5 of 11	ENSP00000255416.4	Q13203
	MYBPH	ENST00000966288.1		c.823G>C	p.Val275Leu	missense	Exon 5 of 10	ENSP00000636347.1
	MYBPH	ENST00000966289.1		c.823G>C	p.Val275Leu	missense	Exon 5 of 11	ENSP00000636348.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	7.0
DANN	Benign	0.62
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.67	N
PhyloP100		0.37
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.048
Sift	Benign	0.56	T
Sift4G	Benign	0.42	T
Polyphen		0.0030	B
Vest4		0.070
MutPred		0.54		Gain of loop (P = 0.1069)
MVP		0.27
MPC		0.13
ClinPred		0.080	T
GERP RS		2.9
Varity_R		0.050
gMVP		0.38
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs139911521; hg19: chr1-203140556;