8-143792008-G-A

Variant names:

• chr8-143792008-G-A
• rs1182163806
• NM_182706.5:c.4640C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_182706.5(SCRIB):​c.4640C>T​(p.Ser1547Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,382,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: SCRIB NM_182706.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.80

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 3 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity SCRIB_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3825756).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCRIB	NM_182706.5	c.4640C>T	p.Ser1547Leu	missense_variant	Exon 33 of 37	ENST00000356994.7	NP_874365.3
SCRIB	NM_015356.5	c.4640C>T	p.Ser1547Leu	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.4640C>T	p.Ser1547Leu	missense_variant	Exon 33 of 37	2	NM_182706.5	ENSP00000349486.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000728 AC: 1 AN: 137440 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 75192

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000261

GnomAD4 exome AF: 0.0000130 AC: 18 AN: 1382464 Hom.: 0 Cov.: 53 AF XY: 0.0000132 AC XY: 9 AN XY: 681230

Gnomad4 AFR exome AF: 0.0000320

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000863

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000395

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000837

Gnomad4 OTH exome AF: 0.0000525

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4640C>T (p.S1547L) alteration is located in exon 33 (coding exon 33) of the SCRIB gene. This alteration results from a C to T substitution at nucleotide position 4640, causing the serine (S) at amino acid position 1547 to be replaced by a leucine (L). 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	0.28
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-0.35	T
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.010	D;D;D
Vest4		0.42
MutPred		0.13		Loss of phosphorylation at S1547 (P = 0.007);Loss of phosphorylation at S1547 (P = 0.007);.;
MVP		0.46
ClinPred		0.76	D
GERP RS		4.8
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1182163806; hg19: chr8-144874178;