3-47418189-C-T

Variant names:

• chr3-47418189-C-T
• rs12487736
• NM_012235.4:c.2392G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.21
• Publications: 58 publications found

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]

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012235.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCAP	NM_012235.4	MANE Select	c.2392G>A	p.Val798Ile	missense	Exon 16 of 23	NP_036367.2
	SCAP	NM_001320044.2		c.1627G>A	p.Val543Ile	missense	Exon 13 of 20	NP_001306973.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCAP	ENST00000265565.10	TSL:1 MANE Select	c.2392G>A	p.Val798Ile	missense	Exon 16 of 23	ENSP00000265565.5
	SCAP	ENST00000648151.1		c.2392G>A	p.Val798Ile	missense	Exon 17 of 24	ENSP00000497087.1
	SCAP	ENST00000320017.10	TSL:2	n.*1109G>A		non_coding_transcript_exon	Exon 11 of 18	ENSP00000324296.6

Frequencies

GnomAD3 genomes AF: 0.478 AC: 72531 AN: 151748 Hom.: 18877 Cov.: 33

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

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.: 66 AF XY: 0.560 AC XY: 394341 AN XY: 704324

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

GnomAD4 genome AF: 0.478 AC: 72564 AN: 151866 Hom.: 18885 Cov.: 33 AF XY: 0.478 AC XY: 35505 AN XY: 74226

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	8.9
DANN	Benign	0.81
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.000010	T
MetaSVM	Benign	-0.90	T
PhyloP100		3.2
Sift4G	Pathogenic	0.0	D
Vest4		0.25
ClinPred		0.016	T
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)

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

Other links and lift over

dbSNP: rs12487736; hg19: chr3-47459679; COSMIC: COSV55542934; COSMIC: COSV55542934;