Genetic Variant NM_182706.5:c.4663G>A (chr8-143791908-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_182706.5(SCRIB):c.4663G>A(p.Gly1555Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0581 in 1,499,702 control chromosomes in the GnomAD database, including 2,810 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.048 ( 185 hom., cov: 29)

Exomes 𝑓: 0.059 ( 2625 hom. )

Consequence

SCRIB
NM_182706.5 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.677

Variant links:

Genes affected

SCRIB (HGNC:30377): (scribble planar cell polarity protein) This gene encodes a protein that was identified as being similar to the Drosophila scribble protein. The mammalian protein is involved in tumor suppression pathways. As a scaffold protein involved in cell polarization processes, this protein binds to many other proteins. The encoded protein binds to papillomavirus E6 protein via its PDZ domain and the C-terminus of E6. Two alternatively spliced transcript variants that encode different protein isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

SCRIB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0011826754).

BP6

Variant 8-143791908-C-T is Benign according to our data. Variant chr8-143791908-C-T is described in ClinVar as [Benign]. Clinvar id is 3060719.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-143791908-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0641 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCRIB	NM_182706.5 link	c.4663G>A	p.Gly1555Ser	missense_variant	Exon 34 of 37	ENST00000356994.7	NP_874365.3	Q14160-3A0A0G2JPP5A0PJK8
SCRIB	NM_015356.5 link	c.4663G>A	p.Gly1555Ser	missense_variant	Exon 34 of 36		NP_056171.3	Q14160-1A0A0G2JNZ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCRIB	ENST00000356994.7 link	c.4663G>A	p.Gly1555Ser	missense_variant	Exon 34 of 37	2	NM_182706.5	ENSP00000349486.2		Q14160-3

Frequencies

GnomAD3 genomes

AF:

0.0477

AC:

6913

AN:

144972

Hom.:

185

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0214

Gnomad AMI

AF:

0.115

Gnomad AMR

AF:

0.0408

Gnomad ASJ

AF:

0.0466

Gnomad EAS

AF:

0.0209

Gnomad SAS

AF:

0.0359

Gnomad FIN

AF:

0.0517

Gnomad MID

AF:

0.0617

Gnomad NFE

AF:

0.0658

Gnomad OTH

AF:

0.0490

GnomAD3 exomes

AF:

0.0500

AC:

7646

AN:

153072

Hom.:

228

AF XY:

0.0510

AC XY:

4268

AN XY:

83678

show subpopulations

Gnomad AFR exome

AF:

0.0189

Gnomad AMR exome

AF:

0.0289

Gnomad ASJ exome

AF:

0.0550

Gnomad EAS exome

AF:

0.0276

Gnomad SAS exome

AF:

0.0349

Gnomad FIN exome

AF:

0.0548

Gnomad NFE exome

AF:

0.0664

Gnomad OTH exome

AF:

0.0529

GnomAD4 exome

AF:

0.0592

AC:

80202

AN:

1354636

Hom.:

2625

Cov.:

AF XY:

0.0588

AC XY:

38959

AN XY:

662526

show subpopulations

Gnomad4 AFR exome

AF:

0.0172

Gnomad4 AMR exome

AF:

0.0310

Gnomad4 ASJ exome

AF:

0.0531

Gnomad4 EAS exome

AF:

0.0237

Gnomad4 SAS exome

AF:

0.0370

Gnomad4 FIN exome

AF:

0.0621

Gnomad4 NFE exome

AF:

0.0641

Gnomad4 OTH exome

AF:

0.0558

GnomAD4 genome

AF:

0.0476

AC:

6912

AN:

145066

Hom.:

185

Cov.:

AF XY:

0.0459

AC XY:

3244

AN XY:

70638

show subpopulations

Gnomad4 AFR

AF:

0.0214

Gnomad4 AMR

AF:

0.0407

Gnomad4 ASJ

AF:

0.0466

Gnomad4 EAS

AF:

0.0207

Gnomad4 SAS

AF:

0.0360

Gnomad4 FIN

AF:

0.0517

Gnomad4 NFE

AF:

0.0658

Gnomad4 OTH

AF:

0.0484

Alfa

AF:

0.0563

Hom.:

Bravo

AF:

0.0459

ESP6500AA

AF:

0.0170

AC:

ESP6500EA

AF:

0.0578

AC:

469

ExAC

AF:

0.0454

AC:

5364

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

SCRIB-related disorder

Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.56

CADD

Benign

5.1

DANN

Benign

0.88

DEOGEN2

Benign

0.057

.;T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0085

MetaRNN

Benign

0.0012

T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.53

N;N;N

REVEL

Benign

0.039

Sift

Benign

0.56

T;T;T

Sift4G

Benign

0.63

T;T;T

Vest4

0.082

ClinPred

0.00035

GERP RS

-2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

gMVP

0.098

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over