chr8-143791676-T-G

Variant names:

• chr8-143791676-T-G
• rs782676114
• NM_182706.5:c.4760A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_182706.5(SCRIB):​c.4760A>C​(p.Tyr1587Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1587C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SCRIB NM_182706.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.25
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41837806).

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.4760A>C	p.Tyr1587Ser	missense	Exon 35 of 37	NP_874365.3
	SCRIB	NM_015356.5		c.4695+200A>C		intron	N/A	NP_056171.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCRIB	ENST00000356994.7	TSL:2 MANE Select	c.4760A>C	p.Tyr1587Ser	missense	Exon 35 of 37	ENSP00000349486.2	Q14160-3
	SCRIB	ENST00000320476.7	TSL:1	c.4695+200A>C		intron	N/A	ENSP00000322938.3	Q14160-1
	SCRIB	ENST00000377533.7	TSL:1	c.4452+200A>C		intron	N/A	ENSP00000366756.3	Q14160-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453562 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 721604

African (AFR) AF: 0.00 AC: 0 AN: 33314

American (AMR) AF: 0.00 AC: 0 AN: 44490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39416

South Asian (SAS) AF: 0.00 AC: 0 AN: 86118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106108

Other (OTH) AF: 0.00 AC: 0 AN: 59976

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Benign	0.93
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.91	T
PhyloP100		1.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.15
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.013	D
Vest4		0.56
MutPred		0.24		Gain of relative solvent accessibility (P = 0.005)
MVP		0.31
ClinPred		0.48	T
GERP RS		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.16
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs782676114; hg19: chr8-144873846;