Genetic Variant HMGCR:c.1722+45A>C (chr5-75355259-A-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025): 2P and 0B. O3_Moderate

The NM_000859.3(HMGCR):c.1722+45A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The gene HMGCR is a known oncogene (CancerMine: 9 oncogene citations). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Consequence

HMGCR
NM_000859.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.624

Publications

0 publications found

Variant links:

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]

HMGCR Gene-Disease associations (from GenCC):

autosomal recessive limb-girdle muscular dystrophy
Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, ClinGen
muscular dystrophy, limb-girdle, autosomal recessive 28
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P

HMGCR links:

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new If you want to explore the variant's impact on the transcript NM_000859.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 points.

Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000859.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HMGCR	NM_000859.3	MANE Select	c.1722+45A>C	intron	N/A	NP_000850.1	P04035-1
HMGCR	NM_001364187.1		c.1722+45A>C	intron	N/A	NP_001351116.1	P04035-1
HMGCR	NM_001130996.2		c.1564-106A>C	intron	N/A	NP_001124468.1	P04035-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HMGCR	ENST00000287936.9	TSL:1 MANE Select	c.1722+45A>C	intron	N/A	ENSP00000287936.4	P04035-1
HMGCR	ENST00000343975.9	TSL:1	c.1564-106A>C	intron	N/A	ENSP00000340816.5	P04035-2
HMGCR	ENST00000511206.5	TSL:2	c.1722+45A>C	intron	N/A	ENSP00000426745.1	P04035-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

7.4

(source)

DANN

Benign

0.45

PhyloP100

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACGS-UK Somatic Oncogenicity v2025

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over