Genetic Variant IQSEC3:p.Gly263Ser (chr12-125796-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001170738.2(IQSEC3):c.787G>A(p.Gly263Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0109 in 1,522,940 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0064 ( 5 hom., cov: 33)

Exomes 𝑓: 0.011 ( 120 hom. )

Consequence

IQSEC3
NM_001170738.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.73

Publications

1 publications found

Variant links:

Genes affected

IQSEC3 (HGNC:29193): (IQ motif and Sec7 domain ArfGEF 3) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in several processes, including actin cytoskeleton organization; activation of GTPase activity; and regulation of small GTPase mediated signal transduction. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

IQSEC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00622648).

BP6

Variant 12-125796-G-A is Benign according to our data. Variant chr12-125796-G-A is described in ClinVar as [Benign]. Clinvar id is 2642556.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQSEC3	NM_001170738.2 link	c.787G>A	p.Gly263Ser	missense_variant	Exon 3 of 14	ENST00000538872.6	NP_001164209.1	Q9UPP2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQSEC3	ENST00000538872.6 link	c.787G>A	p.Gly263Ser	missense_variant	Exon 3 of 14	5	NM_001170738.2	ENSP00000437554.1		Q9UPP2-1
IQSEC3	ENST00000382841.2 link	c.-6-12471G>A		intron_variant	Intron 2 of 12	2		ENSP00000372292.2		Q9UPP2-2

Frequencies

GnomAD3 genomes

AF:

0.00643

AC:

979

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00186

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0122

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0109

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00800

AC:

963

AN:

120334

AF XY:

0.00882

show subpopulations

Gnomad AFR exome

AF:

0.00162

Gnomad AMR exome

AF:

0.00179

Gnomad ASJ exome

AF:

0.0115

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00308

Gnomad NFE exome

AF:

0.0116

Gnomad OTH exome

AF:

0.00731

GnomAD4 exome

AF:

0.0114

AC:

15625

AN:

1370622

Hom.:

120

Cov.:

AF XY:

0.0113

AC XY:

7629

AN XY:

675724

show subpopulations

African (AFR)

AF:

0.00127

AC:

AN:

30632

American (AMR)

AF:

0.00167

AC:

AN:

34188

Ashkenazi Jewish (ASJ)

AF:

0.0122

AC:

295

AN:

24220

East Asian (EAS)

AF:

0.0000567

AC:

AN:

35244

South Asian (SAS)

AF:

0.0118

AC:

918

AN:

77744

European-Finnish (FIN)

AF:

0.00306

AC:

102

AN:

33288

Middle Eastern (MID)

AF:

0.00283

AC:

AN:

4596

European-Non Finnish (NFE)

AF:

0.0128

AC:

13698

AN:

1073532

Other (OTH)

AF:

0.00876

AC:

501

AN:

57178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

952

1904

2857

3809

4761

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00643

AC:

980

AN:

152318

Hom.:

Cov.:

AF XY:

0.00649

AC XY:

483

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00185

AC:

AN:

41566

American (AMR)

AF:

0.00144

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.0124

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00160

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0109

AC:

741

AN:

68020

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

108

161

215

269

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00880

Hom.:

Bravo

AF:

0.00606

TwinsUK

AF:

0.0159

AC:

ALSPAC

AF:

0.0130

AC:

ESP6500AA

AF:

0.000801

AC:

ESP6500EA

AF:

0.00845

AC:

ExAC

AF:

0.00430

AC:

380

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

IQSEC3: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0095

Eigen

Benign

-0.033

Eigen_PC

Benign

0.080

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0062

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

4.7

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.1

REVEL

Benign

0.12

Sift

Benign

0.46

Sift4G

Benign

0.74

Vest4

0.15

MVP

0.47

MPC

0.51

ClinPred

0.024

GERP RS

4.4

Varity_R

0.050

gMVP

0.17

Mutation Taster

=100/0

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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12-125796-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over