5-75341886-A-T

Variant names:

• chr5-75341886-A-T
• rs10038095
• NM_000859.3:c.-23-697A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000859.3(HMGCR):​c.-23-697A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 152,026 control chromosomes in the GnomAD database, including 11,387 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.38 (11387 hom., cov: 32)
• Consequence: HMGCR NM_000859.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.110
• Publications: 13 publications found

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):

• muscular dystrophy, limb-girdle, autosomal recessive 28

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGCR	NM_000859.3	c.-23-697A>T		intron_variant	Intron 1 of 19	ENST00000287936.9	NP_000850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGCR	ENST00000287936.9	c.-23-697A>T		intron_variant	Intron 1 of 19	1	NM_000859.3	ENSP00000287936.4

Frequencies

GnomAD3 genomes AF: 0.382 AC: 58062 AN: 151908 Hom.: 11381 Cov.: 32

Gnomad AFR AF: 0.324

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.384

Gnomad ASJ AF: 0.460

Gnomad EAS AF: 0.532

Gnomad SAS AF: 0.582

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.369

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.382 AC: 58103 AN: 152026 Hom.: 11387 Cov.: 32 AF XY: 0.390 AC XY: 28992 AN XY: 74316

African (AFR) AF: 0.324 AC: 13444 AN: 41472

American (AMR) AF: 0.385 AC: 5877 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.460 AC: 1595 AN: 3466

East Asian (EAS) AF: 0.532 AC: 2745 AN: 5160

South Asian (SAS) AF: 0.581 AC: 2803 AN: 4826

European-Finnish (FIN) AF: 0.441 AC: 4650 AN: 10554

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.379 AC: 25773 AN: 67954

Other (OTH) AF: 0.368 AC: 777 AN: 2112

Alfa AF: 0.385 Hom.: 1430

Bravo AF: 0.370

Asia WGS AF: 0.546 AC: 1894 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Benign	0.90
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10038095; hg19: chr5-74637711;