chr5-75344257-T-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PP2PP3_ModerateBS1_Supporting

The NM_000859.3(HMGCR):c.290T>A(p.Leu97His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000339 in 1,594,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

HMGCR
NM_000859.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.99

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

muscular dystrophy, limb-girdle, autosomal recessive 28
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P
autosomal recessive limb-girdle muscular dystrophy
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

HMGCR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 5 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 3.7591 (above the threshold of 3.09). Trascript score misZ: 4.2252 (above the threshold of 3.09). GenCC associations: The gene is linked to muscular dystrophy, limb-girdle, autosomal recessive 28.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.867

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000361 (52/1442086) while in subpopulation SAS AF = 0.000236 (20/84718). AF 95% confidence interval is 0.000156. There are 0 homozygotes in GnomAdExome4. There are 38 alleles in the male GnomAdExome4 subpopulation. Median coverage is 27. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HMGCR	NM_000859.3	MANE Select	c.290T>A	p.Leu97His	missense	Exon 4 of 20	NP_000850.1	P04035-1
HMGCR	NM_001364187.1		c.290T>A	p.Leu97His	missense	Exon 4 of 20	NP_001351116.1	P04035-1
HMGCR	NM_001130996.2		c.290T>A	p.Leu97His	missense	Exon 4 of 19	NP_001124468.1	P04035-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HMGCR	ENST00000287936.9	TSL:1 MANE Select	c.290T>A	p.Leu97His	missense	Exon 4 of 20	ENSP00000287936.4	P04035-1
HMGCR	ENST00000343975.9	TSL:1	c.290T>A	p.Leu97His	missense	Exon 4 of 19	ENSP00000340816.5	P04035-2
HMGCR	ENST00000511206.5	TSL:2	c.290T>A	p.Leu97His	missense	Exon 4 of 20	ENSP00000426745.1	P04035-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000404

AC:

AN:

247478

AF XY:

0.0000374

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000361

AC:

AN:

1442086

Hom.:

Cov.:

AF XY:

0.0000529

AC XY:

AN XY:

718332

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32964

American (AMR)

AF:

0.00

AC:

AN:

43912

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25944

East Asian (EAS)

AF:

0.0000508

AC:

AN:

39408

South Asian (SAS)

AF:

0.000236

AC:

AN:

84718

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.0000219

AC:

AN:

1096336

Other (OTH)

AF:

0.000100

AC:

AN:

59726

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.430

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74388

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68012

Other (OTH)

AF:

0.000478

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.97

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.87

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.7

PhyloP100

8.0

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-5.8

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.94

MutPred

0.58

Loss of stability (P = 0.0143)

MVP

0.98

MPC

2.2

ClinPred

0.71

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.90

gMVP

0.96

Mutation Taster

=20/80

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over