15-76376206-T-C

Variant names:

• chr15-76376206-T-C
• rs199940124
• NM_020843.4:c.3811A>G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_020843.4(SCAPER):​c.3811A>G​(p.Ile1271Val) variant causes a missense change. The variant allele was found at a frequency of 0.000555 in 1,613,868 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (3 hom.)
• Consequence: SCAPER NM_020843.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 5.89

Genes affected

SCAPER (HGNC:13081): (S-phase cyclin A associated protein in the ER) Predicted to enable nucleic acid binding activity and zinc ion binding activity. Located in cytosol and nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1388937).
• BP6: Variant 15-76376206-T-C is Benign according to our data. Variant chr15-76376206-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 733361.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000361 (55/152180) while in subpopulation NFE AF= 0.000676 (46/68028). AF 95% confidence interval is 0.000521. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCAPER	NM_020843.4	c.3811A>G	p.Ile1271Val	missense_variant	Exon 29 of 32	ENST00000563290.6	NP_065894.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCAPER	ENST00000563290.6	c.3811A>G	p.Ile1271Val	missense_variant	Exon 29 of 32	5	NM_020843.4	ENSP00000454973.1
SCAPER	ENST00000324767.11	c.3811A>G	p.Ile1271Val	missense_variant	Exon 28 of 31	1		ENSP00000326924.7
SCAPER	ENST00000538941.6	c.3073A>G	p.Ile1025Val	missense_variant	Exon 29 of 32	1		ENSP00000442190.2

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000317 AC: 79 AN: 249098 Hom.: 1 AF XY: 0.000333 AC XY: 45 AN XY: 135128

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000371

Gnomad NFE exome AF: 0.000558

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000575 AC: 841 AN: 1461688 Hom.: 3 Cov.: 30 AF XY: 0.000576 AC XY: 419 AN XY: 727124

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.000749

Gnomad4 NFE exome AF: 0.000689

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 19 AN XY: 74346

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000572 Hom.: 0

Bravo AF: 0.000355

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000359 AC: 3

ExAC AF: 0.000356 AC: 43

EpiCase AF: 0.000273

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Mar 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3811A>G (p.I1271V) alteration is located in exon 28 (coding exon 28) of the SCAPER gene. This alteration results from a A to G substitution at nucleotide position 3811, causing the isoleucine (I) at amino acid position 1271 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

SCAPER-related disorder Uncertain:1

Jul 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SCAPER c.3829A>G variant is predicted to result in the amino acid substitution p.Ile1277Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.058% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T;.;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;.;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.63	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.26	T;T;T
Sift4G	Benign	0.23	T;D;T
Vest4		0.40
MVP		0.37
MPC		0.25
ClinPred		0.068	T
GERP RS		5.8
Varity_R		0.15
gMVP		0.23

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: rs199940124; hg19: chr15-76668547;