3-47414586-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012235.4(SCAP):c.3373G>A(p.Val1125Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00029 in 1,613,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: SCAP NM_012235.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.58

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15620998).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCAP	NM_012235.4	c.3373G>A	p.Val1125Met	missense_variant	21/23	ENST00000265565.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCAP	ENST00000265565.10	c.3373G>A	p.Val1125Met	missense_variant	21/23	1	NM_012235.4	P1
SCAP	ENST00000648151.1	c.3373G>A	p.Val1125Met	missense_variant	22/24			P1
SCAP	ENST00000320017.10	c.*2087G>A		3_prime_UTR_variant, NMD_transcript_variant	16/18	2
SCAP	ENST00000441517.6	c.*2519G>A		3_prime_UTR_variant, NMD_transcript_variant	18/20	2

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000355 AC: 89 AN: 250814 Hom.: 0 AF XY: 0.000332 AC XY: 45 AN XY: 135746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000654

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000292 AC: 426 AN: 1461114 Hom.: 0 Cov.: 32 AF XY: 0.000268 AC XY: 195 AN XY: 726862

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000759

Gnomad4 NFE exome AF: 0.000356

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74494

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000380 Hom.: 0

Bravo AF: 0.000257

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000379 AC: 46

EpiCase AF: 0.000436

EpiControl AF: 0.000593

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

Oct 31, 2022

The c.3373G>A (p.V1125M) alteration is located in exon 21 (coding exon 20) of the SCAP gene. This alteration results from a G to A substitution at nucleotide position 3373, causing the valine (V) at amino acid position 1125 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	Benign	0.25
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.9	L;.;L
MutationTaster	Benign	0.53	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.42	N;.;.
REVEL	Benign	0.26
Sift	Benign	0.17	T;.;.
Sift4G	Uncertain	0.016	D;D;.
Polyphen		0.99	D;.;D
Vest4		0.61
MVP		0.63
MPC		0.82
ClinPred		0.073	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.067
gMVP		0.31

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: rs201148221; hg19: chr3-47456076; COSMIC: COSV55546307; COSMIC: COSV55546307;