Genetic Variant SCAP:p.Val798Ile (chr3-47418189-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_012235.4(SCAP):c.2392G>A(p.Val798Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.552 in 1,574,632 control chromosomes in the GnomAD database, including 244,920 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.48 ( 18885 hom., cov: 33)

Exomes 𝑓: 0.56 ( 226035 hom. )

Consequence

SCAP
NM_012235.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.21

Publications

58 publications found

Variant links:

Genes affected

SCAP (HGNC:30634): (SREBF chaperone) This gene encodes a protein with a sterol sensing domain (SSD) and seven WD domains. In the presence of cholesterol, this protein binds to sterol regulatory element binding proteins (SREBPs) and mediates their transport from the ER to the Golgi. The SREBPs are then proteolytically cleaved and regulate sterol biosynthesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

SCAP 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 (MetaRNN=1.0460712E-5).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCAP	NM_012235.4 link	c.2392G>A	p.Val798Ile	missense_variant	Exon 16 of 23	ENST00000265565.10	NP_036367.2	Q12770-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCAP	ENST00000265565.10 link	c.2392G>A	p.Val798Ile	missense_variant	Exon 16 of 23	1	NM_012235.4	ENSP00000265565.5		Q12770-1

Frequencies

GnomAD3 genomes

AF:

0.478

AC:

72531

AN:

151748

Hom.:

18877

Cov.:

show subpopulations

Gnomad AFR

AF:

0.264

Gnomad AMI

AF:

0.471

Gnomad AMR

AF:

0.484

Gnomad ASJ

AF:

0.504

Gnomad EAS

AF:

0.470

Gnomad SAS

AF:

0.522

Gnomad FIN

AF:

0.617

Gnomad MID

AF:

0.487

Gnomad NFE

AF:

0.581

Gnomad OTH

AF:

0.489

GnomAD2 exomes

AF:

0.541

AC:

100584

AN:

185836

AF XY:

0.546

show subpopulations

Gnomad AFR exome

AF:

0.283

Gnomad AMR exome

AF:

0.502

Gnomad ASJ exome

AF:

0.507

Gnomad EAS exome

AF:

0.481

Gnomad FIN exome

AF:

0.625

Gnomad NFE exome

AF:

0.590

Gnomad OTH exome

AF:

0.551

GnomAD4 exome

AF:

0.560

AC:

797215

AN:

1422766

Hom.:

226035

Cov.:

AF XY:

0.560

AC XY:

394341

AN XY:

704324

show subpopulations

African (AFR)

AF:

0.263

AC:

8552

AN:

32562

American (AMR)

AF:

0.497

AC:

19539

AN:

39332

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

12687

AN:

25374

East Asian (EAS)

AF:

0.502

AC:

18866

AN:

37572

South Asian (SAS)

AF:

0.526

AC:

42809

AN:

81422

European-Finnish (FIN)

AF:

0.610

AC:

29906

AN:

48996

Middle Eastern (MID)

AF:

0.466

AC:

2665

AN:

5716

European-Non Finnish (NFE)

AF:

0.577

AC:

630881

AN:

1092876

Other (OTH)

AF:

0.531

AC:

31310

AN:

58916

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

22104

44207

66311

88414

110518

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.478

AC:

72564

AN:

151866

Hom.:

18885

Cov.:

AF XY:

0.478

AC XY:

35505

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.264

AC:

10948

AN:

41396

American (AMR)

AF:

0.485

AC:

7406

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.504

AC:

1749

AN:

3468

East Asian (EAS)

AF:

0.469

AC:

2409

AN:

5134

South Asian (SAS)

AF:

0.520

AC:

2509

AN:

4822

European-Finnish (FIN)

AF:

0.617

AC:

6539

AN:

10594

Middle Eastern (MID)

AF:

0.480

AC:

141

AN:

294

European-Non Finnish (NFE)

AF:

0.581

AC:

39396

AN:

67854

Other (OTH)

AF:

0.491

AC:

1037

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1819

3638

5456

7275

9094

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.551

Hom.:

36484

Bravo

AF:

0.457

ESP6500AA

AF:

0.271

AC:

1178

ESP6500EA

AF:

0.568

AC:

4846

ExAC

AF:

0.491

AC:

56790

Asia WGS

AF:

0.531

AC:

1845

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.65

CADD

Benign

8.9

(source)

DANN

Benign

0.81

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.46

MetaRNN

Benign

0.000010

MetaSVM

Benign

-0.90

PhyloP100

3.2

Sift4G

Pathogenic

0.0

Vest4

0.25

ClinPred

0.016

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.061

Mutation Taster

=92/8

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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chr3-47418189-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over