5-75357012-C-T

Variant names:

• chr5-75357012-C-T
• rs188153918
• NM_000859.3:c.1986+564C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_000859.3(HMGCR):​c.1986+564C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 398,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (0 hom.)
• Consequence: HMGCR NM_000859.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.15
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015853643).
• BP6: Variant 5-75357012-C-T is Benign according to our data. Variant chr5-75357012-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2578980.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00179 (273/152214) while in subpopulation NFE AF = 0.0031 (211/68024). AF 95% confidence interval is 0.00276. There are 0 homozygotes in GnomAd4. There are 111 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1986+564C>T		intron	N/A	NP_000850.1	P04035-1
	HMGCR	NM_001364187.1		c.1986+564C>T		intron	N/A	NP_001351116.1	P04035-1
	HMGCR	NM_001130996.2		c.1827+564C>T		intron	N/A	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.1986+564C>T		intron	N/A	ENSP00000287936.4	P04035-1
	HMGCR	ENST00000343975.9	TSL:1	c.1827+564C>T		intron	N/A	ENSP00000340816.5	P04035-2
	CERT1	ENST00000863484.1		c.*10G>A		splice_region	Exon 18 of 18	ENSP00000533543.1

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 273 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00310

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.00217 AC: 533 AN: 246036 Hom.: 0 Cov.: 0 AF XY: 0.00233 AC XY: 290 AN XY: 124682

African (AFR) AF: 0.000418 AC: 3 AN: 7174

American (AMR) AF: 0.00175 AC: 13 AN: 7430

Ashkenazi Jewish (ASJ) AF: 0.00195 AC: 18 AN: 9222

East Asian (EAS) AF: 0.00 AC: 0 AN: 22880

South Asian (SAS) AF: 0.00462 AC: 14 AN: 3030

European-Finnish (FIN) AF: 0.000529 AC: 11 AN: 20808

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1292

European-Non Finnish (NFE) AF: 0.00277 AC: 437 AN: 157848

Other (OTH) AF: 0.00226 AC: 37 AN: 16352

GnomAD4 genome AF: 0.00179 AC: 273 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.00149 AC XY: 111 AN XY: 74426

African (AFR) AF: 0.000530 AC: 22 AN: 41520

American (AMR) AF: 0.00157 AC: 24 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4818

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00310 AC: 211 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.00201 Hom.: 0

Bravo AF: 0.00181

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00311 AC: 12

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_noAF	Benign	-0.94
CADD	Benign	13
DANN	Benign	0.71
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.016	T
PhyloP100		-1.1
GERP RS		-3.1
Mutation Taster		=100/0	polymorphism

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: rs188153918; hg19: chr5-74652837;