3-12901182-G-A

Variant names:

• chr3-12901182-G-A
• rs1694241056
• NM_001134382.3:c.3146C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001134382.3(IQSEC1):​c.3146C>T​(p.Pro1049Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000072 in 1,389,800 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: IQSEC1 NM_001134382.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.33
• Publications: 0 publications found

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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000297478 (HGNC:):

ACMG classification

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=0.14849481).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC1	NM_001134382.3	MANE Select	c.3146C>T	p.Pro1049Leu	missense	Exon 14 of 14	NP_001127854.1	Q6DN90-3
	IQSEC1	NM_001376938.2		c.3470C>T	p.Pro1157Leu	missense	Exon 16 of 16	NP_001363867.1	A0A3B3IRZ4
	IQSEC1	NM_001330619.3		c.*327C>T		3_prime_UTR	Exon 13 of 13	NP_001317548.1	A0A0C4DGT3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC1	ENST00000613206.2	TSL:2 MANE Select	c.3146C>T	p.Pro1049Leu	missense	Exon 14 of 14	ENSP00000480301.1	Q6DN90-3
	IQSEC1	ENST00000618604.4	TSL:1	c.*327C>T		3_prime_UTR	Exon 13 of 13	ENSP00000478001.1	A0A0C4DGT3
	IQSEC1	ENST00000273221.8	TSL:1	c.2847+1591C>T		intron	N/A	ENSP00000273221.4	Q6DN90-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.20e-7 AC: 1 AN: 1389800 Hom.: 0 Cov.: 34 AF XY: 0.00000146 AC XY: 1 AN XY: 685580

African (AFR) AF: 0.00 AC: 0 AN: 31452

American (AMR) AF: 0.00 AC: 0 AN: 35590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24980

East Asian (EAS) AF: 0.00 AC: 0 AN: 35696

South Asian (SAS) AF: 0.00 AC: 0 AN: 78878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5624

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1073802

Other (OTH) AF: 0.0000173 AC: 1 AN: 57732

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Benign	0.91
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.90	T
PhyloP100		3.3
PrimateAI	Uncertain	0.71	T
Sift4G	Uncertain	0.056	T
Vest4		0.25
MVP		0.18
ClinPred		0.29	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
gMVP		0.26
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs1694241056; hg19: chr3-12942681;