8-143792000-G-A

Variant names:

• chr8-143792000-G-A
• rs1456263629
• NM_182706.5:c.4648C>T

Variant summary

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

The NM_182706.5(SCRIB):​c.4648C>T​(p.Pro1550Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000728 in 1,373,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P1550A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: SCRIB NM_182706.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.71
• 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=0.41449395).

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.4648C>T	p.Pro1550Ser	missense	Exon 33 of 37	NP_874365.3
	SCRIB	NM_015356.5		c.4648C>T	p.Pro1550Ser	missense	Exon 33 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.4648C>T	p.Pro1550Ser	missense	Exon 33 of 37	ENSP00000349486.2	Q14160-3
	SCRIB	ENST00000320476.7	TSL:1	c.4648C>T	p.Pro1550Ser	missense	Exon 33 of 36	ENSP00000322938.3	Q14160-1
	SCRIB	ENST00000377533.7	TSL:1	c.4405C>T	p.Pro1469Ser	missense	Exon 33 of 36	ENSP00000366756.3	Q14160-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.28e-7 AC: 1 AN: 1373266 Hom.: 0 Cov.: 52 AF XY: 0.00000148 AC XY: 1 AN XY: 675374

African (AFR) AF: 0.00 AC: 0 AN: 31000

American (AMR) AF: 0.00 AC: 0 AN: 32080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22448

East Asian (EAS) AF: 0.00 AC: 0 AN: 36272

South Asian (SAS) AF: 0.00 AC: 0 AN: 74036

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45462

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5184

European-Non Finnish (NFE) AF: 9.35e-7 AC: 1 AN: 1069988

Other (OTH) AF: 0.00 AC: 0 AN: 56796

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	-0.22	T
PhyloP100		6.7
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.19
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.24	T
Vest4		0.45
MutPred		0.11		Gain of phosphorylation at P1550 (P = 0.0079)
MVP		0.67
ClinPred		0.91	D
GERP RS		4.8
gMVP		0.37
Mutation Taster		=58/42	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: rs1456263629; hg19: chr8-144874170;