8-143791209-C-A

Variant names:

• chr8-143791209-C-A
• NM_182706.5:c.4922G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_182706.5(SCRIB):​c.4922G>T​(p.Arg1641Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • 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: 1.58

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31051812).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCRIB	NM_182706.5	c.4922G>T	p.Arg1641Leu	missense_variant	Exon 37 of 37	ENST00000356994.7	NP_874365.3
SCRIB	NM_015356.5	c.4847G>T	p.Arg1616Leu	missense_variant	Exon 36 of 36		NP_056171.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCRIB	ENST00000356994.7	c.4922G>T	p.Arg1641Leu	missense_variant	Exon 37 of 37	2	NM_182706.5	ENSP00000349486.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1296474 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 627812

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.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4922G>T (p.R1641L) alteration is located in exon 37 (coding exon 37) of the SCRIB gene. This alteration results from a G to T substitution at nucleotide position 4922, causing the arginine (R) at amino acid position 1641 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	Uncertain	0.37
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	.;T;T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-0.32	T
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.48
MutPred		0.21		.;Loss of MoRF binding (P = 0.0286);.;
MVP		0.52
ClinPred		0.70	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
gMVP		0.082

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-144873379;