Genetic Variant IQSEC1:p.Pro995Leu (chr3-12901344-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001134382.3(IQSEC1):c.2984C>T(p.Pro995Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P995S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

IQSEC1
NM_001134382.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.73

Publications

0 publications found

Variant links:

Genes affected

IQSEC1 (HGNC:29112): (IQ motif and Sec7 domain ArfGEF 1) Predicted to enable protein kinase binding activity. Predicted to be involved in several processes, including positive regulation of focal adhesion disassembly; positive regulation of keratinocyte migration; and regulation of postsynaptic neurotransmitter receptor internalization. Located in nucleolus. Implicated in intellectual developmental disorder with short stature and behavioral abnormalities. [provided by Alliance of Genome Resources, Apr 2022]

IQSEC1 Gene-Disease associations (from GenCC):

intellectual developmental disorder with short stature and behavioral abnormalities
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

IQSEC1 links:

ENSG00000297478 (HGNC:):

ENSG00000297478 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.103070945).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134382.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IQSEC1	NM_001134382.3	MANE Select	c.2984C>T	p.Pro995Leu	missense	Exon 14 of 14	NP_001127854.1	Q6DN90-3
IQSEC1	NM_001376938.2		c.3308C>T	p.Pro1103Leu	missense	Exon 16 of 16	NP_001363867.1	A0A3B3IRZ4
IQSEC1	NM_001330619.3		c.*165C>T		3_prime_UTR	Exon 13 of 13	NP_001317548.1	A0A0C4DGT3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IQSEC1	ENST00000613206.2	TSL:2 MANE Select	c.2984C>T	p.Pro995Leu	missense	Exon 14 of 14	ENSP00000480301.1	Q6DN90-3
IQSEC1	ENST00000618604.4	TSL:1	c.*165C>T		3_prime_UTR	Exon 13 of 13	ENSP00000478001.1	A0A0C4DGT3
IQSEC1	ENST00000273221.8	TSL:1	c.2847+1429C>T		intron	N/A	ENSP00000273221.4	Q6DN90-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1377134

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

680202

African (AFR)

AF:

0.00

AC:

AN:

31256

American (AMR)

AF:

0.00

AC:

AN:

35548

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24936

East Asian (EAS)

AF:

0.00

AC:

AN:

35420

South Asian (SAS)

AF:

0.00

AC:

AN:

78870

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41484

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5392

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1066824

Other (OTH)

AF:

0.00

AC:

AN:

57404

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

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

0.089

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.40

DEOGEN2

Benign

0.059

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.61

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.0

PhyloP100

1.7

PrimateAI

Uncertain

0.68

Sift4G

Uncertain

0.032

Vest4

0.26

MVP

0.068

ClinPred

0.056

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.26

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

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