NM_000859.3:c.1190T>C

Variant names:

• chr5-75351424-T-C
• rs1760412911
• NM_000859.3:c.1190T>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000859.3(HMGCR):​c.1190T>C​(p.Val397Ala) variant causes a missense, splice region 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. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HMGCR NM_000859.3 missense, splice_region
• Scores: Splicing: ADA: 0.00006548
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.461

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04386425).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGCR	NM_000859.3	c.1190T>C	p.Val397Ala	missense_variant, splice_region_variant	Exon 11 of 20	ENST00000287936.9	NP_000850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGCR	ENST00000287936.9	c.1190T>C	p.Val397Ala	missense_variant, splice_region_variant	Exon 11 of 20	1	NM_000859.3	ENSP00000287936.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1190T>C (p.V397A) alteration is located in exon 11 (coding exon 10) of the HMGCR gene. This alteration results from a T to C substitution at nucleotide position 1190, causing the valine (V) at amino acid position 397 to be replaced by an alanine (A). 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	0.078
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.9
DANN	Benign	0.72
DEOGEN2	Benign	0.23	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.53	.;T;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.044	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.40	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.32	N;N;N
REVEL	Benign	0.049
Sift	Benign	0.78	T;T;T
Sift4G	Benign	0.75	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.055
MutPred		0.24		Loss of methylation at K396 (P = 0.048);Loss of methylation at K396 (P = 0.048);Loss of methylation at K396 (P = 0.048);
MVP		0.25
MPC		0.99
ClinPred		0.028	T
GERP RS		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.016
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000065
dbscSNV1_RF	Benign	0.010
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: rs1760412911; hg19: chr5-74647249;