5-75359474-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_000859.3(HMGCR):c.2375A>G(p.Tyr792Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: HMGCR NM_000859.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.05

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]

CERT1 (HGNC:2205): (ceramide transporter 1) This gene encodes a kinase that specifically phosphorylates the N-terminal region of the non-collagenous domain of the alpha 3 chain of type IV collagen, known as the Goodpasture antigen. Goodpasture disease is the result of an autoimmune response directed at this antigen. One isoform of this protein is also involved in ceramide intracellular transport. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, HMGCR
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848
• PP5: Variant 5-75359474-A-G is Pathogenic according to our data. Variant chr5-75359474-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 2506433.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-75359474-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMGCR	NM_000859.3	c.2375A>G	p.Tyr792Cys	missense_variant	18/20	ENST00000287936.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMGCR	ENST00000287936.9	c.2375A>G	p.Tyr792Cys	missense_variant	18/20	1	NM_000859.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461686 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Muscular dystrophy, limb-girdle, autosomal recessive 28 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;D;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Pathogenic	3.2	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.6	D;D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.014	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.76
MutPred		0.61		Loss of catalytic residue at Y792 (P = 0.0793);Loss of catalytic residue at Y792 (P = 0.0793);.;
MVP		0.65
MPC		2.1
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.93
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr5-74655299;