chr5-75345615-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_000859.3(HMGCR):​c.407G>A​(p.Arg136Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HMGCR
NM_000859.3 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.67
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HMGCR. . Gene score misZ 3.7591 (greater than the threshold 3.09). Trascript score misZ 4.2252 (greater than threshold 3.09). GenCC has associacion of gene with muscular dystrophy, limb-girdle, autosomal recessive 28.
BP4
Computational evidence support a benign effect (MetaRNN=0.105896264).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HMGCRNM_000859.3 linkuse as main transcriptc.407G>A p.Arg136Lys missense_variant 5/20 ENST00000287936.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HMGCRENST00000287936.9 linkuse as main transcriptc.407G>A p.Arg136Lys missense_variant 5/201 NM_000859.3 P1P04035-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251224
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135782
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460832
Hom.:
0
Cov.:
28
AF XY:
0.00000275
AC XY:
2
AN XY:
726812
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 01, 2023The c.407G>A (p.R136K) alteration is located in exon 5 (coding exon 4) of the HMGCR gene. This alteration results from a G to A substitution at nucleotide position 407, causing the arginine (R) at amino acid position 136 to be replaced by a lysine (K). 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
0.086
BayesDel_addAF
Benign
-0.016
T
BayesDel_noAF
Benign
-0.16
CADD
Benign
21
DANN
Benign
0.85
DEOGEN2
Uncertain
0.60
D;D;.
Eigen
Benign
-0.32
Eigen_PC
Benign
-0.014
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.80
.;T;D
M_CAP
Benign
0.028
D
MetaRNN
Benign
0.11
T;T;T
MetaSVM
Uncertain
-0.14
T
MutationAssessor
Benign
-1.7
N;N;N
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
2.0
N;N;N
REVEL
Uncertain
0.40
Sift
Benign
1.0
T;T;T
Sift4G
Benign
1.0
T;T;T
Polyphen
0.0030
B;B;B
Vest4
0.18
MutPred
0.66
Gain of ubiquitination at R136 (P = 0.0238);Gain of ubiquitination at R136 (P = 0.0238);Gain of ubiquitination at R136 (P = 0.0238);
MVP
0.70
MPC
0.84
ClinPred
0.32
T
GERP RS
5.7
Varity_R
0.21
gMVP
0.50

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs781639869; hg19: chr5-74641440; API