3-47414981-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_012235.4(SCAP):c.3152G>A(p.Arg1051Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000146 in 1,439,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: SCAP NM_012235.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.02

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a modified_residue Omega-N-methylarginine (size 0) in uniprot entity SCAP_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18576062).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCAP	NM_012235.4	c.3152G>A	p.Arg1051Gln	missense_variant	20/23	ENST00000265565.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCAP	ENST00000265565.10	c.3152G>A	p.Arg1051Gln	missense_variant	20/23	1	NM_012235.4	P1
SCAP	ENST00000648151.1	c.3152G>A	p.Arg1051Gln	missense_variant	21/24			P1
SCAP	ENST00000320017.10	c.*1866G>A		3_prime_UTR_variant, NMD_transcript_variant	15/18	2
SCAP	ENST00000441517.6	c.*2298G>A		3_prime_UTR_variant, NMD_transcript_variant	17/20	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000870 AC: 2 AN: 229978 Hom.: 0 AF XY: 0.0000160 AC XY: 2 AN XY: 124706

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 SAS exome AF: 0.0000369

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000951

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000146 AC: 21 AN: 1439376 Hom.: 0 Cov.: 33 AF XY: 0.00000979 AC XY: 7 AN XY: 714952

Gnomad4 AFR exome AF: 0.0000307

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000480

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000109

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2022

The c.3152G>A (p.R1051Q) alteration is located in exon 20 (coding exon 19) of the SCAP gene. This alteration results from a G to A substitution at nucleotide position 3152, causing the arginine (R) at amino acid position 1051 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.4	M;.;M
MutationTaster	Benign	0.76	D;D;D
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.9	N;.;.
REVEL	Benign	0.10
Sift	Benign	0.035	D;.;.
Sift4G	Benign	0.17	T;T;.
Polyphen		0.057	B;.;B
Vest4		0.32
MutPred		0.33		Loss of methylation at R1051 (P = 0.0152);.;Loss of methylation at R1051 (P = 0.0152);
MVP		0.77
MPC		0.31
ClinPred		0.79	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.46

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: rs201451588; hg19: chr3-47456471;