chr5-75359673-T-G

Variant names:

• chr5-75359673-T-G
• rs17238540
• NM_000859.3:c.2457+117T>G

Variant summary

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

The NM_000859.3(HMGCR):​c.2457+117T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0257 in 909,748 control chromosomes in the GnomAD database, including 480 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as no classification for the single variant (no stars).

• Frequency:
  • Genomes: 𝑓 0.038 (198 hom., cov: 32)
  • Exomes 𝑓: 0.023 (282 hom.)
• Consequence: HMGCR NM_000859.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.185
• Publications: 54 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0808 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCR	NM_000859.3	MANE Select	c.2457+117T>G		intron	N/A	NP_000850.1
	HMGCR	NM_001364187.1		c.2457+117T>G		intron	N/A	NP_001351116.1
	HMGCR	NM_001130996.2		c.2298+117T>G		intron	N/A	NP_001124468.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCR	ENST00000287936.9	TSL:1 MANE Select	c.2457+117T>G		intron	N/A	ENSP00000287936.4
	HMGCR	ENST00000343975.9	TSL:1	c.2298+117T>G		intron	N/A	ENSP00000340816.5
	HMGCR	ENST00000509085.5	TSL:1	c.286-312T>G		intron	N/A	ENSP00000421378.1

Frequencies

GnomAD3 genomes AF: 0.0383 AC: 5831 AN: 152202 Hom.: 198 Cov.: 32

Gnomad AFR AF: 0.0832

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0224

Gnomad ASJ AF: 0.0355

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0245

Gnomad OTH AF: 0.0383

GnomAD4 exome AF: 0.0231 AC: 17534 AN: 757428 Hom.: 282 Cov.: 10 AF XY: 0.0222 AC XY: 8613 AN XY: 387356

African (AFR) AF: 0.0863 AC: 1574 AN: 18234

American (AMR) AF: 0.0212 AC: 454 AN: 21430

Ashkenazi Jewish (ASJ) AF: 0.0397 AC: 637 AN: 16040

East Asian (EAS) AF: 0.0000599 AC: 2 AN: 33400

South Asian (SAS) AF: 0.00415 AC: 221 AN: 53218

European-Finnish (FIN) AF: 0.0165 AC: 741 AN: 44916

Middle Eastern (MID) AF: 0.0554 AC: 146 AN: 2634

European-Non Finnish (NFE) AF: 0.0239 AC: 12699 AN: 531540

Other (OTH) AF: 0.0294 AC: 1060 AN: 36016

GnomAD4 genome AF: 0.0383 AC: 5840 AN: 152320 Hom.: 198 Cov.: 32 AF XY: 0.0361 AC XY: 2688 AN XY: 74480

African (AFR) AF: 0.0832 AC: 3456 AN: 41560

American (AMR) AF: 0.0223 AC: 342 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0355 AC: 123 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4828

European-Finnish (FIN) AF: 0.0127 AC: 135 AN: 10622

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0245 AC: 1670 AN: 68034

Other (OTH) AF: 0.0374 AC: 79 AN: 2110

Alfa AF: 0.0294 Hom.: 253

Bravo AF: 0.0418

Asia WGS AF: 0.00866 AC: 31 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.6
DANN	Benign	0.40
PhyloP100		0.18
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: rs17238540; hg19: chr5-74655498;