chr5-75354650-CCTT-C
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4_SupportingPP5
The NM_000859.3(HMGCR):c.1522_1524del(p.Ser508del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00000137 in 1,461,014 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
HMGCR
NM_000859.3 inframe_deletion
NM_000859.3 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.65
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_000859.3. Strenght limited to Supporting due to length of the change: 1aa.
PP5
?
Variant 5-75354650-CCTT-C is Pathogenic according to our data. Variant chr5-75354650-CCTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 2506435.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-75354650-CCTT-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HMGCR | NM_000859.3 | c.1522_1524del | p.Ser508del | inframe_deletion | 12/20 | ENST00000287936.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HMGCR | ENST00000287936.9 | c.1522_1524del | p.Ser508del | inframe_deletion | 12/20 | 1 | NM_000859.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461014Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 726854
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GnomAD4 genome ? Cov.: 33
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Bravo
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
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
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at