Variant chr12-125823-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001170738.2(IQSEC3):c.814C>T(p.Arg272Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,529,514 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

IQSEC3
NM_001170738.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.08

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.020136744).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IQSEC3	NM_001170738.2 linkuse as main transcript	c.814C>T	p.Arg272Trp	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.814C>T	p.Arg272Trp	missense_variant	3/14	5	NM_001170738.2	ENSP00000437554.1		Q9UPP2-1
IQSEC3	ENST00000382841.2 linkuse as main transcript	c.-6-12444C>T		intron_variant		2		ENSP00000372292.2		Q9UPP2-2

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000238

AC:

AN:

126230

Hom.:

AF XY:

0.000159

AC XY:

AN XY:

69200

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000837

Gnomad ASJ exome

AF:

0.00283

Gnomad EAS exome

AF:

0.000199

Gnomad SAS exome

AF:

0.0000453

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000419

Gnomad OTH exome

AF:

0.000258

GnomAD4 exome

AF:

0.000173

AC:

238

AN:

1377194

Hom.:

Cov.:

AF XY:

0.000163

AC XY:

111

AN XY:

679468

show subpopulations

Gnomad4 AFR exome

AF:

0.0000323

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.00230

Gnomad4 EAS exome

AF:

0.000113

Gnomad4 SAS exome

AF:

0.0000634

Gnomad4 FIN exome

AF:

0.0000598

Gnomad4 NFE exome

AF:

0.000142

Gnomad4 OTH exome

AF:

0.000226

GnomAD4 genome

AF:

0.000144

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000304

Hom.:

Bravo

AF:

0.000174

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000129

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

Jan 26, 2023

The c.814C>T (p.R272W) 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 814, causing the arginine (R) at amino acid position 272 to be replaced by a tryptophan (W). 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

0.084

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.56

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.42

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.38

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.077

MetaRNN

Benign

0.020

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.14

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Vest4

0.21

MutPred

0.30

Gain of catalytic residue at P275 (P = 0.0042);

MVP

0.24

MPC

0.95

ClinPred

0.24

GERP RS

2.4

Varity_R

0.093

gMVP

0.38

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