5-43294058-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_001098272.3(HMGCS1):c.1181C>G(p.Pro394Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000139 in 1,577,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P394T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

HMGCS1
NM_001098272.3 missense, splice_region

Scores

Splicing: ADA: 0.8615

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.34

Publications

0 publications found

Variant links:

Genes affected

HMGCS1 (HGNC:5007): (3-hydroxy-3-methylglutaryl-CoA synthase 1) Enables protein homodimerization activity. Predicted to be involved in acetyl-CoA metabolic process and farnesyl diphosphate biosynthetic process, mevalonate pathway. Predicted to be located in cytoplasm. Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

HMGCS1 Gene-Disease associations (from GenCC):

rigid spine syndrome
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

HMGCS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 6 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.0389 (below the threshold of 3.09). Trascript score misZ: 4.1249 (above the threshold of 3.09). GenCC associations: The gene is linked to rigid spine syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.832

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098272.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HMGCS1	NM_001098272.3	MANE Select	c.1181C>G	p.Pro394Arg	missense splice_region	Exon 8 of 11	NP_001091742.1	Q01581
HMGCS1	NM_001324219.2		c.1181C>G	p.Pro394Arg	missense splice_region	Exon 7 of 10	NP_001311148.1	Q01581
HMGCS1	NM_001324220.2		c.1181C>G	p.Pro394Arg	missense splice_region	Exon 8 of 11	NP_001311149.1	Q01581

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HMGCS1	ENST00000325110.11	TSL:1 MANE Select	c.1181C>G	p.Pro394Arg	missense splice_region	Exon 8 of 11	ENSP00000322706.6	Q01581
HMGCS1	ENST00000715988.1		c.1232C>G	p.Pro411Arg	missense splice_region	Exon 8 of 11	ENSP00000520550.1	A0ABB0MV10
HMGCS1	ENST00000433297.2	TSL:5	c.1181C>G	p.Pro394Arg	missense splice_region	Exon 7 of 10	ENSP00000399402.2	Q01581

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152016

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:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251036

AF XY:

0.0000147

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:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000147

AC:

AN:

1425962

Hom.:

Cov.:

AF XY:

0.0000169

AC XY:

AN XY:

711672

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32778

American (AMR)

AF:

0.00

AC:

AN:

44656

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25906

East Asian (EAS)

AF:

0.00

AC:

AN:

39546

South Asian (SAS)

AF:

0.00

AC:

AN:

85590

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.0000195

AC:

AN:

1079192

Other (OTH)

AF:

0.00

AC:

AN:

59210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.406

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:

0.00000658

AC:

AN:

152016

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74252

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41384

American (AMR)

AF:

0.00

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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:

0.00

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.69

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

0.096

MutationAssessor

Pathogenic

3.0

PhyloP100

9.3

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.75

Sift

Uncertain

0.010

Sift4G

Uncertain

0.046

Polyphen

0.99

Vest4

0.77

MVP

0.68

MPC

2.1

ClinPred

0.94

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.71

gMVP

0.67

Mutation Taster

=49/51

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.86

dbscSNV1_RF

Benign

0.52

SpliceAI score (max)

0.10

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