Genetic Variant SCRIB:p.Arg1647His (chr8-143791191-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_182706.5(SCRIB):c.4940G>A(p.Arg1647His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000278 in 1,438,780 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 0.000059 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

SCRIB
NM_182706.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.222

Publications

1 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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22278482).

BS2

High AC in GnomAd4 at 9 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.4940G>A	p.Arg1647His	missense	Exon 37 of 37	NP_874365.3
	SCRIB	NM_015356.5		c.4865G>A	p.Arg1622His	missense	Exon 36 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.4940G>A	p.Arg1647His	missense	Exon 37 of 37	ENSP00000349486.2	Q14160-3
SCRIB	ENST00000320476.7	TSL:1	c.4865G>A	p.Arg1622His	missense	Exon 36 of 36	ENSP00000322938.3	Q14160-1
SCRIB	ENST00000377533.7	TSL:1	c.4622G>A	p.Arg1541His	missense	Exon 36 of 36	ENSP00000366756.3	Q14160-2

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000543

AC:

AN:

73648

AF XY:

0.0000276

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000206

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000133

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000336

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000241

AC:

AN:

1286592

Hom.:

Cov.:

AF XY:

0.0000145

AC XY:

AN XY:

621714

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27812

American (AMR)

AF:

0.000214

AC:

AN:

18674

Ashkenazi Jewish (ASJ)

AF:

0.0000535

AC:

AN:

18682

East Asian (EAS)

AF:

0.0000295

AC:

AN:

33888

South Asian (SAS)

AF:

0.0000339

AC:

AN:

59008

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4986

European-Non Finnish (NFE)

AF:

0.0000224

AC:

AN:

1026102

Other (OTH)

AF:

0.00

AC:

AN:

53104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000591

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41450

American (AMR)

AF:

0.000327

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68018

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.0000638

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000904

AC:

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

Uncertain

0.39

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Benign

0.62

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.29

PhyloP100

0.22

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.8

REVEL

Benign

0.19

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.38

MVP

0.52

ClinPred

0.23

GERP RS

4.2

gMVP

0.058

Mutation Taster

=85/15

polymorphism

(source)

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

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