chr8-143791252-C-T

Variant names:

• chr8-143791252-C-T
• rs782521316
• NM_182706.5:c.4879G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_182706.5(SCRIB):​c.4879G>A​(p.Gly1627Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000996 in 1,505,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. G1627V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: SCRIB NM_182706.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.33
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.045357734).
• BS2: High AC in GnomAdExome4 at 12 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.4879G>A	p.Gly1627Ser	missense	Exon 37 of 37	NP_874365.3
	SCRIB	NM_015356.5		c.4804G>A	p.Gly1602Ser	missense	Exon 36 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.4879G>A	p.Gly1627Ser	missense	Exon 37 of 37	ENSP00000349486.2	Q14160-3
	SCRIB	ENST00000320476.7	TSL:1	c.4804G>A	p.Gly1602Ser	missense	Exon 36 of 36	ENSP00000322938.3	Q14160-1
	SCRIB	ENST00000377533.7	TSL:1	c.4561G>A	p.Gly1521Ser	missense	Exon 36 of 36	ENSP00000366756.3	Q14160-2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152168 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000227 AC: 3 AN: 132398 AF XY: 0.0000143

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000551

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000887 AC: 12 AN: 1353374 Hom.: 0 Cov.: 31 AF XY: 0.0000121 AC XY: 8 AN XY: 663332

African (AFR) AF: 0.00 AC: 0 AN: 29870

American (AMR) AF: 0.0000360 AC: 1 AN: 27762

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20808

East Asian (EAS) AF: 0.00 AC: 0 AN: 36594

South Asian (SAS) AF: 0.0000423 AC: 3 AN: 70964

European-Finnish (FIN) AF: 0.0000212 AC: 1 AN: 47078

Middle Eastern (MID) AF: 0.000184 AC: 1 AN: 5424

European-Non Finnish (NFE) AF: 0.00000283 AC: 3 AN: 1059134

Other (OTH) AF: 0.0000538 AC: 3 AN: 55740

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152168 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74336

African (AFR) AF: 0.0000724 AC: 3 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.00000844 AC: 1

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	0.063
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	2.7
DANN	Benign	0.56
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.049	N
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.069
Sift	Benign	0.18	T
Sift4G	Benign	0.65	T
Vest4		0.042
MutPred		0.050		Loss of catalytic residue at G1602 (P = 0.0396)
MVP		0.59
ClinPred		0.038	T
GERP RS		-0.0015
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.038
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs782521316; hg19: chr8-144873422;