Variant chr12-125767-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001170738.2(IQSEC3):c.758C>T(p.Pro253Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000481 in 1,512,584 control chromosomes in the GnomAD database, including 2 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00050 ( 2 hom. )

Consequence

IQSEC3
NM_001170738.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.12

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 made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11215782).

BS2

High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IQSEC3	NM_001170738.2 linkuse as main transcript	c.758C>T	p.Pro253Leu	missense_variant	3/14	ENST00000538872.6	NP_001164209.1	Q9UPP2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IQSEC3	ENST00000538872.6 linkuse as main transcript	c.758C>T	p.Pro253Leu	missense_variant	3/14	5	NM_001170738.2	ENSP00000437554.1		Q9UPP2-1
IQSEC3	ENST00000382841.2 linkuse as main transcript	c.-6-12500C>T		intron_variant		2		ENSP00000372292.2		Q9UPP2-2

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000298

AC:

AN:

110634

Hom.:

AF XY:

0.000300

AC XY:

AN XY:

60088

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000237

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000104

Gnomad SAS exome

AF:

0.000278

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000513

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000495

AC:

674

AN:

1360406

Hom.:

Cov.:

AF XY:

0.000520

AC XY:

348

AN XY:

669712

show subpopulations

Gnomad4 AFR exome

AF:

0.000198

Gnomad4 AMR exome

AF:

0.000278

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000170

Gnomad4 SAS exome

AF:

0.000253

Gnomad4 FIN exome

AF:

0.0000911

Gnomad4 NFE exome

AF:

0.000563

Gnomad4 OTH exome

AF:

0.000494

GnomAD4 genome

AF:

0.000348

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.000956

Alfa

AF:

0.000128

Hom.:

Bravo

AF:

0.000438

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000370

AC:

ESP6500EA

AF:

0.000157

AC:

ExAC

AF:

0.000147

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2023

The c.758C>T (p.P253L) alteration is located in exon 3 (coding exon 3) of the IQSEC3 gene. This alteration results from a C to T substitution at nucleotide position 758, causing the proline (P) at amino acid position 253 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.74

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.020

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.69

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.55

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.9

REVEL

Benign

0.079

Sift

Benign

0.10

Sift4G

Benign

0.21

Vest4

0.28

MVP

0.30

MPC

0.41

ClinPred

0.070

GERP RS

1.1

Varity_R

0.034

gMVP

0.20

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over