3-47418189-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0460712E-5).
• BP6: Variant 3-47418189-C-T is Benign according to our data. Variant chr3-47418189-C-T is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
SCAP	NM_012235.4	c.2392G>A	p.Val798Ile	missense_variant	16/23	ENST00000265565.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCAP	ENST00000265565.10	c.2392G>A	p.Val798Ile	missense_variant	16/23	1	NM_012235.4	P1
SCAP	ENST00000648151.1	c.2392G>A	p.Val798Ile	missense_variant	17/24			P1
SCAP	ENST00000320017.10	c.*1109G>A		3_prime_UTR_variant, NMD_transcript_variant	11/18	2
SCAP	ENST00000441517.6	c.*1541G>A		3_prime_UTR_variant, NMD_transcript_variant	13/20	2

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

GnomAD3 exomes AF: 0.541 AC: 100584 AN: 185836 Hom.: 27854 AF XY: 0.546 AC XY: 54951 AN XY: 100734

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 SAS exome AF: 0.527

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

Gnomad4 AFR exome AF: 0.263

Gnomad4 AMR exome AF: 0.497

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.502

Gnomad4 SAS exome AF: 0.526

Gnomad4 FIN exome AF: 0.610

Gnomad4 NFE exome AF: 0.577

Gnomad4 OTH exome AF: 0.531

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

Gnomad4 AFR AF: 0.264

Gnomad4 AMR AF: 0.485

Gnomad4 ASJ AF: 0.504

Gnomad4 EAS AF: 0.469

Gnomad4 SAS AF: 0.520

Gnomad4 FIN AF: 0.617

Gnomad4 NFE AF: 0.581

Gnomad4 OTH AF: 0.491

Alfa AF: 0.545 Hom.: 8464

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	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
MutationTaster	Benign	0.023	P;P;P
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

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

LitVar

Other links and lift over

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