Genetic Variant SCRIB:p.Pro1550Ala (chr8-143792000-G-C) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_182706.5(SCRIB):c.4648C>G(p.Pro1550Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000017 in 1,525,394 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 (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000073 ( 0 hom. )

Consequence

SCRIB
NM_182706.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.71

Publications

0 publications found

Variant links:

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

SCRIB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.2768405).

BS2

High AC in GnomAd4 at 16 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.4648C>G	p.Pro1550Ala	missense	Exon 33 of 37	NP_874365.3
	SCRIB	NM_015356.5		c.4648C>G	p.Pro1550Ala	missense	Exon 33 of 36	NP_056171.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCRIB	ENST00000356994.7	TSL:2 MANE Select	c.4648C>G	p.Pro1550Ala	missense	Exon 33 of 37	ENSP00000349486.2	Q14160-3
SCRIB	ENST00000320476.7	TSL:1	c.4648C>G	p.Pro1550Ala	missense	Exon 33 of 36	ENSP00000322938.3	Q14160-1
SCRIB	ENST00000377533.7	TSL:1	c.4405C>G	p.Pro1469Ala	missense	Exon 33 of 36	ENSP00000366756.3	Q14160-2

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000776

AC:

AN:

128852

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000277

GnomAD4 exome

AF:

0.00000728

AC:

AN:

1373266

Hom.:

Cov.:

AF XY:

0.00000296

AC XY:

AN XY:

675374

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31000

American (AMR)

AF:

0.0000623

AC:

AN:

32080

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22448

East Asian (EAS)

AF:

0.00

AC:

AN:

36272

South Asian (SAS)

AF:

0.00

AC:

AN:

74036

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45462

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5184

European-Non Finnish (NFE)

AF:

0.00000561

AC:

AN:

1069988

Other (OTH)

AF:

0.0000352

AC:

AN:

56796

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000105

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41430

American (AMR)

AF:

0.000982

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000230

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.016

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.94

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.40

PhyloP100

6.7

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.8

REVEL

Benign

0.20

Sift

Uncertain

0.0070

Sift4G

Benign

0.16

Vest4

0.38

MutPred

0.12

Gain of relative solvent accessibility (P = 0.1066)

MVP

0.64

ClinPred

0.63

GERP RS

4.8

gMVP

0.25

Mutation Taster

=55/45

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over