chr5-75350940-A-C

Position:

• chr5-75350940-A-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_000859.3(HMGCR):​c.932A>C​(p.Tyr311Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000699 in 1,613,224 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00083 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (10 hom.)
• Consequence: HMGCR NM_000859.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 7.31

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 Benign. Variant got -8 ACMG points.

• 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=0.01021263).
• BP6: Variant 5-75350940-A-C is Benign according to our data. Variant chr5-75350940-A-C is described in ClinVar as [Benign]. Clinvar id is 3053372.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMGCR	NM_000859.3	c.932A>C	p.Tyr311Ser	missense_variant	9/20	ENST00000287936.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMGCR	ENST00000287936.9	c.932A>C	p.Tyr311Ser	missense_variant	9/20	1	NM_000859.3	P1

Frequencies

GnomAD3 genomes AF: 0.000828 AC: 126 AN: 152194 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0158

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00156 AC: 389 AN: 250052 Hom.: 4 AF XY: 0.00148 AC XY: 200 AN XY: 135184

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.000300

Gnomad EAS exome AF: 0.0151

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000685 AC: 1001 AN: 1460912 Hom.: 10 Cov.: 31 AF XY: 0.000654 AC XY: 475 AN XY: 726776

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.000192

Gnomad4 EAS exome AF: 0.0156

Gnomad4 SAS exome AF: 0.00109

Gnomad4 FIN exome AF: 0.00200

Gnomad4 NFE exome AF: 0.000116

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000827 AC: 126 AN: 152312 Hom.: 3 Cov.: 32 AF XY: 0.000886 AC XY: 66 AN XY: 74484

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0158

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000916 Hom.: 4

Bravo AF: 0.000763

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00178 AC: 216

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

HMGCR-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 29, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Uncertain	0.71	D;D;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	.;D;D
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.6	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Uncertain	0.34
Sift	Benign	0.057	T;T;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.18	B;B;P
Vest4		0.74
MVP		0.50
MPC		1.5
ClinPred		0.089	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs191835914; hg19: chr5-74646765;