8-143791886-G-A

Variant names:

• chr8-143791886-G-A
• rs370154381
• NM_182706.5:c.4685C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_182706.5(SCRIB):​c.4685C>T​(p.Pro1562Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000425 in 1,528,230 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1562Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: SCRIB NM_182706.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.08
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27954745).
• BS2: High AC in GnomAdExome4 at 61 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182706.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCRIB	NM_182706.5	MANE Select	c.4685C>T	p.Pro1562Leu	missense	Exon 34 of 37	NP_874365.3
	SCRIB	NM_015356.5		c.4685C>T	p.Pro1562Leu	missense	Exon 34 of 36	NP_056171.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCRIB	ENST00000356994.7	TSL:2 MANE Select	c.4685C>T	p.Pro1562Leu	missense	Exon 34 of 37	ENSP00000349486.2	Q14160-3
	SCRIB	ENST00000320476.7	TSL:1	c.4685C>T	p.Pro1562Leu	missense	Exon 34 of 36	ENSP00000322938.3	Q14160-1
	SCRIB	ENST00000377533.7	TSL:1	c.4442C>T	p.Pro1481Leu	missense	Exon 34 of 36	ENSP00000366756.3	Q14160-2

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151586 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000585

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000582 AC: 10 AN: 171824 AF XY: 0.0000423

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000446

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000334

Gnomad FIN exome AF: 0.0000634

Gnomad NFE exome AF: 0.0000250

Gnomad OTH exome AF: 0.000250

GnomAD4 exome AF: 0.0000443 AC: 61 AN: 1376644 Hom.: 0 Cov.: 36 AF XY: 0.0000370 AC XY: 25 AN XY: 675388

African (AFR) AF: 0.00 AC: 0 AN: 30680

American (AMR) AF: 0.0000311 AC: 1 AN: 32180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21524

East Asian (EAS) AF: 0.000104 AC: 4 AN: 38348

South Asian (SAS) AF: 0.0000133 AC: 1 AN: 74942

European-Finnish (FIN) AF: 0.0000822 AC: 4 AN: 48690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5362

European-Non Finnish (NFE) AF: 0.0000384 AC: 41 AN: 1068472

Other (OTH) AF: 0.000177 AC: 10 AN: 56446

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151586 Hom.: 0 Cov.: 29 AF XY: 0.0000405 AC XY: 3 AN XY: 73992

African (AFR) AF: 0.00 AC: 0 AN: 41240

American (AMR) AF: 0.00 AC: 0 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000585 AC: 3 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67814

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.000889 Hom.: 0

ExAC AF: 0.0000671 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	-0.24	T
PhyloP100		3.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.010	D
Vest4		0.45
MutPred		0.12		Loss of glycosylation at P1562 (P = 0.084)
MVP		0.71
ClinPred		0.45	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.30
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs370154381; hg19: chr8-144874056; COSMIC: COSV108135724; COSMIC: COSV108135724;