5-75351540-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_000859.3(HMGCR):c.1306A>G(p.Ile436Val) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HMGCR NM_000859.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.397

Genes affected

HMGCR (HGNC:5006): (3-hydroxy-3-methylglutaryl-CoA reductase) HMG-CoA reductase is the rate-limiting enzyme for cholesterol synthesis and is regulated via a negative feedback mechanism mediated by sterols and non-sterol metabolites derived from mevalonate, the product of the reaction catalyzed by reductase. Normally in mammalian cells this enzyme is suppressed by cholesterol derived from the internalization and degradation of low density lipoprotein (LDL) via the LDL receptor. Competitive inhibitors of the reductase induce the expression of LDL receptors in the liver, which in turn increases the catabolism of plasma LDL and lowers the plasma concentration of cholesterol, an important determinant of atherosclerosis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, HMGCR
• BP4: Computational evidence support a benign effect (MetaRNN=0.04919353).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMGCR	NM_000859.3	c.1306A>G	p.Ile436Val	missense_variant	11/20	ENST00000287936.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMGCR	ENST00000287936.9	c.1306A>G	p.Ile436Val	missense_variant	11/20	1	NM_000859.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2024

The c.1306A>G (p.I436V) alteration is located in exon 11 (coding exon 10) of the HMGCR gene. This alteration results from a A to G substitution at nucleotide position 1306, causing the isoleucine (I) at amino acid position 436 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	3.0
Dann	Benign	0.70
DEOGEN2	Benign	0.23	T;T;.
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.19	N
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.049	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.020	N;N;N
REVEL	Benign	0.014
Sift	Benign	0.39	T;T;T
Sift4G	Benign	0.86	T;T;T
Polyphen		0.017	B;B;B
Vest4		0.11
MutPred		0.20		Gain of phosphorylation at T431 (P = 0.1703);Gain of phosphorylation at T431 (P = 0.1703);Gain of phosphorylation at T431 (P = 0.1703);
MVP		0.30
MPC		0.69
ClinPred		0.068	T
GERP RS		0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.022
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-74647365;