chr3-12901104-C-T

Variant names:

• chr3-12901104-C-T
• NM_001134382.3:c.3224G>A

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.3224G>A​(p.Gly1075Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000721 in 1,386,236 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: 1.04
• 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=0.08464533).

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.3224G>A	p.Gly1075Asp	missense	Exon 14 of 14	NP_001127854.1	Q6DN90-3
	IQSEC1	NM_001376938.2		c.3548G>A	p.Gly1183Asp	missense	Exon 16 of 16	NP_001363867.1	A0A3B3IRZ4
	IQSEC1	NM_001330619.3		c.*405G>A		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.3224G>A	p.Gly1075Asp	missense	Exon 14 of 14	ENSP00000480301.1	Q6DN90-3
	IQSEC1	ENST00000618604.4	TSL:1	c.*405G>A		3_prime_UTR	Exon 13 of 13	ENSP00000478001.1	A0A0C4DGT3
	IQSEC1	ENST00000273221.8	TSL:1	c.2847+1669G>A		intron	N/A	ENSP00000273221.4	Q6DN90-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.21e-7 AC: 1 AN: 1386236 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 683716

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31464

American (AMR) AF: 0.00 AC: 0 AN: 35352

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24804

East Asian (EAS) AF: 0.00 AC: 0 AN: 35676

South Asian (SAS) AF: 0.00 AC: 0 AN: 78732

European-Finnish (FIN) AF: 0.0000248 AC: 1 AN: 40348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5430

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1076714

Other (OTH) AF: 0.00 AC: 0 AN: 57716

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

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	0.24
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Benign	0.74
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.0
PrimateAI	Uncertain	0.74	T
Sift4G	Benign	0.78	T
Vest4		0.22
MVP		0.12
ClinPred		0.035	T
GERP RS		-0.049
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.20
Mutation Taster		=100/0	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

hg19: chr3-12942603;