Genetic Variant NM_020843.4:c.3811A>G (chr15-76376206-T-C) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 5.89

Publications

3 publications found

Variant links:

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]

SCAPER Gene-Disease associations (from GenCC):

intellectual developmental disorder and retinitis pigmentosa; IDDRP
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
neurodevelopmental disorder
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Bardet-Biedl syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SCAPER links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 733361.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020843.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCAPER	NM_020843.4	MANE Select	c.3811A>G	p.Ile1271Val	missense	Exon 29 of 32	NP_065894.2	Q9BY12-1
SCAPER	NM_001353009.2		c.3829A>G	p.Ile1277Val	missense	Exon 30 of 33	NP_001339938.1
SCAPER	NM_001353011.2		c.3427A>G	p.Ile1143Val	missense	Exon 30 of 33	NP_001339940.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCAPER	ENST00000563290.6	TSL:5 MANE Select	c.3811A>G	p.Ile1271Val	missense	Exon 29 of 32	ENSP00000454973.1	Q9BY12-1
SCAPER	ENST00000324767.11	TSL:1	c.3811A>G	p.Ile1271Val	missense	Exon 28 of 31	ENSP00000326924.7	Q9BY12-1
SCAPER	ENST00000538941.6	TSL:1	c.3073A>G	p.Ile1025Val	missense	Exon 29 of 32	ENSP00000442190.2	Q9BY12-3

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000317

AC:

AN:

249098

AF XY:

0.000333

show subpopulations

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 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.:

Cov.:

AF XY:

0.000576

AC XY:

419

AN XY:

727124

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000928

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.000749

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000689

AC:

766

AN:

1111852

Other (OTH)

AF:

0.000348

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

143

191

239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000361

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41426

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000676

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000541

Hom.:

Bravo

AF:

0.000355

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000359

AC:

ExAC

AF:

0.000356

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Inborn genetic diseases (1)

SCAPER-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.012

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.0085

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

PhyloP100

5.9

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.63

REVEL

Benign

0.18

Sift

Benign

0.26

Sift4G

Benign

0.23

Vest4

0.40

MVP

0.37

MPC

0.25

ClinPred

0.068

GERP RS

5.8

Varity_R

0.15

gMVP

0.23

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over