Genetic Variant HMGCR:c.780+56T>A (chr5-75350430-T-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000859.3(HMGCR):c.780+56T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0568 in 1,190,780 control chromosomes in the GnomAD database, including 2,458 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 0.055 ( 304 hom., cov: 32)

Exomes 𝑓: 0.057 ( 2154 hom. )

Consequence

HMGCR
NM_000859.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.263

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGCR	NM_000859.3 link	c.780+56T>A		intron_variant	Intron 8 of 19	ENST00000287936.9	NP_000850.1	P04035-1A0A024RAP2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGCR	ENST00000287936.9 link	c.780+56T>A		intron_variant	Intron 8 of 19	1	NM_000859.3	ENSP00000287936.4		P04035-1

Frequencies

GnomAD3 genomes

AF:

0.0552

AC:

8393

AN:

152104

Hom.:

303

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0322

Gnomad AMI

AF:

0.0275

Gnomad AMR

AF:

0.0751

Gnomad ASJ

AF:

0.0167

Gnomad EAS

AF:

0.183

Gnomad SAS

AF:

0.0319

Gnomad FIN

AF:

0.0850

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0544

Gnomad OTH

AF:

0.0551

GnomAD4 exome

AF:

0.0570

AC:

59199

AN:

1038558

Hom.:

2154

AF XY:

0.0556

AC XY:

29541

AN XY:

531506

show subpopulations

African (AFR)

AF:

0.0325

AC:

769

AN:

23672

American (AMR)

AF:

0.0875

AC:

2790

AN:

31882

Ashkenazi Jewish (ASJ)

AF:

0.0177

AC:

376

AN:

21286

East Asian (EAS)

AF:

0.172

AC:

6454

AN:

37624

South Asian (SAS)

AF:

0.0237

AC:

1683

AN:

71042

European-Finnish (FIN)

AF:

0.0850

AC:

4411

AN:

51882

Middle Eastern (MID)

AF:

0.0203

AC:

AN:

4818

European-Non Finnish (NFE)

AF:

0.0534

AC:

40058

AN:

750588

Other (OTH)

AF:

0.0559

AC:

2560

AN:

45764

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

2733

5466

8198

10931

13664

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0552

AC:

8401

AN:

152222

Hom.:

304

Cov.:

AF XY:

0.0575

AC XY:

4276

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0322

AC:

1336

AN:

41552

American (AMR)

AF:

0.0754

AC:

1152

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0167

AC:

AN:

3472

East Asian (EAS)

AF:

0.184

AC:

952

AN:

5186

South Asian (SAS)

AF:

0.0315

AC:

152

AN:

4826

European-Finnish (FIN)

AF:

0.0850

AC:

899

AN:

10580

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0544

AC:

3702

AN:

68006

Other (OTH)

AF:

0.0573

AC:

121

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

386

772

1159

1545

1931

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0547

Hom.:

Bravo

AF:

0.0555

Asia WGS

AF:

0.116

AC:

402

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

4.4

(source)

DANN

Benign

0.37

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Below is the list of publications found by LitVar. It may be empty.

chr5-75350430-T-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over