3-47413883-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_012235.4(SCAP):c.3811G>A(p.Val1271Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCAP NM_012235.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.62

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.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCAP	NM_012235.4	c.3811G>A	p.Val1271Met	missense_variant	23/23	ENST00000265565.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCAP	ENST00000265565.10	c.3811G>A	p.Val1271Met	missense_variant	23/23	1	NM_012235.4	P1
SCAP	ENST00000648151.1	c.3811G>A	p.Val1271Met	missense_variant	24/24			P1
SCAP	ENST00000320017.10	c.*2525G>A		3_prime_UTR_variant, NMD_transcript_variant	18/18	2
SCAP	ENST00000441517.6	c.*2957G>A		3_prime_UTR_variant, NMD_transcript_variant	20/20	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

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

Nov 15, 2023

The c.3811G>A (p.V1271M) alteration is located in exon 23 (coding exon 22) of the SCAP gene. This alteration results from a G to A substitution at nucleotide position 3811, causing the valine (V) at amino acid position 1271 to be replaced by a methionine (M). 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	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.50	D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	1.1	L;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.70	N;.;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.024	D;.;.
Sift4G	Uncertain	0.046	D;D;.
Polyphen		1.0	D;.;D
Vest4		0.66
MutPred		0.49		Gain of loop (P = 0.1069);.;Gain of loop (P = 0.1069);
MVP		0.72
MPC		0.83
ClinPred		0.83	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.21
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1705427739; hg19: chr3-47455373;