3-47414591-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_012235.4(SCAP):c.3368C>T(p.Thr1123Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000924 in 1,461,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: SCAP NM_012235.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.27

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCAP	NM_012235.4	c.3368C>T	p.Thr1123Met	missense_variant	21/23	ENST00000265565.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCAP	ENST00000265565.10	c.3368C>T	p.Thr1123Met	missense_variant	21/23	1	NM_012235.4	P1
SCAP	ENST00000648151.1	c.3368C>T	p.Thr1123Met	missense_variant	22/24			P1
SCAP	ENST00000320017.10	c.*2082C>T		3_prime_UTR_variant, NMD_transcript_variant	16/18	2
SCAP	ENST00000441517.6	c.*2514C>T		3_prime_UTR_variant, NMD_transcript_variant	18/20	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250838 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135756

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000924 AC: 135 AN: 1461126 Hom.: 0 Cov.: 32 AF XY: 0.0000908 AC XY: 66 AN XY: 726864

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000113

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Dec 08, 2023

The c.3368C>T (p.T1123M) alteration is located in exon 21 (coding exon 20) of the SCAP gene. This alteration results from a C to T substitution at nucleotide position 3368, causing the threonine (T) at amino acid position 1123 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	0.74
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.53	D;T;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.1	L;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.5	D;.;.
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D;.;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;.;D
Vest4		0.85
MutPred		0.63		Loss of glycosylation at S1119 (P = 0.011);.;Loss of glycosylation at S1119 (P = 0.011);
MVP		0.78
MPC		0.88
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.64
gMVP		0.64

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: rs770001989; hg19: chr3-47456081; COSMIC: COSV99650895; COSMIC: COSV99650895;