chr8-143792020-G-C

Variant names:

• chr8-143792020-G-C
• rs782539078
• NM_182706.5:c.4628C>G

Variant summary

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

The NM_182706.5(SCRIB):​c.4628C>G​(p.Ala1543Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCRIB NM_182706.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.11

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]

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=0.23872751).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCRIB	NM_182706.5	c.4628C>G	p.Ala1543Gly	missense_variant	Exon 33 of 37	ENST00000356994.7	NP_874365.3
SCRIB	NM_015356.5	c.4628C>G	p.Ala1543Gly	missense_variant	Exon 33 of 36		NP_056171.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCRIB	ENST00000356994.7	c.4628C>G	p.Ala1543Gly	missense_variant	Exon 33 of 37	2	NM_182706.5	ENSP00000349486.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1401700 Hom.: 0 Cov.: 53 AF XY: 0.00 AC XY: 0 AN XY: 692852

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4628C>G (p.A1543G) alteration is located in exon 33 (coding exon 33) of the SCRIB gene. This alteration results from a C to G substitution at nucleotide position 4628, causing the alanine (A) at amino acid position 1543 to be replaced by a glycine (G). 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	0.26
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	.;T;T
Eigen	Benign	0.098
Eigen_PC	Benign	0.052
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.44	T
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.013	D;D;D
Vest4		0.29
MutPred		0.18		Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);.;
MVP		0.37
ClinPred		0.86	D
GERP RS		5.0
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: rs782539078; hg19: chr8-144874190;