chr5-75360350-G-A

Variant names:

• chr5-75360350-G-A
• rs5909
• NM_000859.3:c.*8G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000859.3(HMGCR):​c.*8G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0949 in 1,610,820 control chromosomes in the GnomAD database, including 7,975 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.082 (592 hom., cov: 32)
  • Exomes 𝑓: 0.096 (7383 hom.)
• Consequence: HMGCR NM_000859.3 3_prime_UTR
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.242
• Publications: 46 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]

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]

CERT1 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 34

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 5-75360350-G-A is Benign according to our data. Variant chr5-75360350-G-A is described in ClinVar as Benign. ClinVar VariationId is 3060727.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000859.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCR	NM_000859.3	MANE Select	c.*8G>A		3_prime_UTR	Exon 20 of 20	NP_000850.1	P04035-1
	HMGCR	NM_001364187.1		c.*8G>A		3_prime_UTR	Exon 20 of 20	NP_001351116.1	P04035-1
	HMGCR	NM_001130996.2		c.*8G>A		3_prime_UTR	Exon 19 of 19	NP_001124468.1	P04035-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCR	ENST00000287936.9	TSL:1 MANE Select	c.*8G>A		3_prime_UTR	Exon 20 of 20	ENSP00000287936.4	P04035-1
	HMGCR	ENST00000343975.9	TSL:1	c.*8G>A		3_prime_UTR	Exon 19 of 19	ENSP00000340816.5	P04035-2
	HMGCR	ENST00000509085.5	TSL:1	c.*8G>A		3_prime_UTR	Exon 4 of 4	ENSP00000421378.1	H0Y8K6

Frequencies

GnomAD3 genomes AF: 0.0818 AC: 12431 AN: 152052 Hom.: 591 Cov.: 32

Gnomad AFR AF: 0.0326

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.0276

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0975

Gnomad OTH AF: 0.0708

GnomAD2 exomes AF: 0.104 AC: 25777 AN: 248668 AF XY: 0.105

Gnomad AFR exome AF: 0.0310

Gnomad AMR exome AF: 0.156

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.0269

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.0977

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.0963 AC: 140447 AN: 1458650 Hom.: 7383 Cov.: 31 AF XY: 0.0975 AC XY: 70774 AN XY: 725698

African (AFR) AF: 0.0293 AC: 979 AN: 33418

American (AMR) AF: 0.148 AC: 6603 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 4452 AN: 26090

East Asian (EAS) AF: 0.0188 AC: 747 AN: 39632

South Asian (SAS) AF: 0.124 AC: 10689 AN: 86062

European-Finnish (FIN) AF: 0.110 AC: 5850 AN: 53344

Middle Eastern (MID) AF: 0.0761 AC: 438 AN: 5754

European-Non Finnish (NFE) AF: 0.0947 AC: 105044 AN: 1109464

Other (OTH) AF: 0.0936 AC: 5645 AN: 60318

GnomAD4 genome AF: 0.0817 AC: 12427 AN: 152170 Hom.: 592 Cov.: 32 AF XY: 0.0829 AC XY: 6167 AN XY: 74402

African (AFR) AF: 0.0325 AC: 1350 AN: 41518

American (AMR) AF: 0.116 AC: 1767 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 573 AN: 3470

East Asian (EAS) AF: 0.0271 AC: 140 AN: 5174

South Asian (SAS) AF: 0.120 AC: 578 AN: 4820

European-Finnish (FIN) AF: 0.111 AC: 1179 AN: 10602

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0975 AC: 6627 AN: 67990

Other (OTH) AF: 0.0701 AC: 148 AN: 2112

Alfa AF: 0.0940 Hom.: 3379

Bravo AF: 0.0765

Asia WGS AF: 0.0750 AC: 260 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	HMGCR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.3
DANN	Benign	0.59
PhyloP100		0.24
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: rs5909; hg19: chr5-74656175;