Genetic Variant IQSEC3:p.Ser259Phe (chr12-125785-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001170738.2(IQSEC3):c.776C>T(p.Ser259Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000461 in 1,517,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000044 ( 0 hom. )

Consequence

IQSEC3
NM_001170738.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.67

Publications

2 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:

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ACMG classification

Classification was made for transcript

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=0.29234764).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001170738.2. 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
	IQSEC3	NM_001170738.2	MANE Select	c.776C>T	p.Ser259Phe	missense	Exon 3 of 14	NP_001164209.1	Q9UPP2-1
	IQSEC3	NM_015232.2		c.-6-12482C>T		intron	N/A	NP_056047.1	Q9UPP2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC3	ENST00000538872.6	TSL:5 MANE Select	c.776C>T	p.Ser259Phe	missense	Exon 3 of 14	ENSP00000437554.1	Q9UPP2-1
	IQSEC3	ENST00000382841.2	TSL:2	c.-6-12482C>T		intron	N/A	ENSP00000372292.2	Q9UPP2-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00000869

AC:

AN:

115054

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:

0.0000228

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000439

AC:

AN:

1365328

Hom.:

Cov.:

AF XY:

0.00000297

AC XY:

AN XY:

672770

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30378

American (AMR)

AF:

0.00

AC:

AN:

33112

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23724

East Asian (EAS)

AF:

0.00

AC:

AN:

35230

South Asian (SAS)

AF:

0.00

AC:

AN:

76742

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33096

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4682

European-Non Finnish (NFE)

AF:

0.00000560

AC:

AN:

1071410

Other (OTH)

AF:

0.00

AC:

AN:

56954

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

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

0.093

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.026

Eigen

Benign

0.13

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.60

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.69

PhyloP100

1.7

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.8

REVEL

Benign

0.13

Sift

Uncertain

0.0030

Sift4G

Benign

0.24

Vest4

0.27

MutPred

0.25

Loss of phosphorylation at S259 (P = 0.0054)

MVP

0.31

MPC

0.43

ClinPred

0.41

GERP RS

5.5

Varity_R

0.12

gMVP

0.26

Mutation Taster

=79/21

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over