3-12901126-C-T

Variant names:

• chr3-12901126-C-T
• rs559459711
• NM_001134382.3:c.3202G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001134382.3(IQSEC1):​c.3202G>A​(p.Ala1068Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000683 in 1,541,926 control chromosomes in the GnomAD database, including 10 homozygotes. 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (6 hom.)
• Consequence: IQSEC1 NM_001134382.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0240
• Publications: 1 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00309664).
• BP6: Variant 3-12901126-C-T is Benign according to our data. Variant chr3-12901126-C-T is described in ClinVar as Benign. ClinVar VariationId is 710916.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.3202G>A	p.Ala1068Thr	missense	Exon 14 of 14	NP_001127854.1	Q6DN90-3
	IQSEC1	NM_001376938.2		c.3526G>A	p.Ala1176Thr	missense	Exon 16 of 16	NP_001363867.1	A0A3B3IRZ4
	IQSEC1	NM_001330619.3		c.*383G>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.3202G>A	p.Ala1068Thr	missense	Exon 14 of 14	ENSP00000480301.1	Q6DN90-3
	IQSEC1	ENST00000618604.4	TSL:1	c.*383G>A		3_prime_UTR	Exon 13 of 13	ENSP00000478001.1	A0A0C4DGT3
	IQSEC1	ENST00000273221.8	TSL:1	c.2847+1647G>A		intron	N/A	ENSP00000273221.4	Q6DN90-1

Frequencies

GnomAD3 genomes AF: 0.00345 AC: 524 AN: 151696 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.000740 AC: 104 AN: 140482 AF XY: 0.000606

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.000697

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000187

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000381 AC: 530 AN: 1390112 Hom.: 6 Cov.: 37 AF XY: 0.000338 AC XY: 232 AN XY: 685768

African (AFR) AF: 0.0136 AC: 429 AN: 31522

American (AMR) AF: 0.000845 AC: 30 AN: 35522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24986

East Asian (EAS) AF: 0.00 AC: 0 AN: 35704

South Asian (SAS) AF: 0.0000506 AC: 4 AN: 78996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42172

Middle Eastern (MID) AF: 0.000179 AC: 1 AN: 5576

European-Non Finnish (NFE) AF: 0.0000195 AC: 21 AN: 1077782

Other (OTH) AF: 0.000778 AC: 45 AN: 57852

GnomAD4 genome AF: 0.00345 AC: 523 AN: 151814 Hom.: 4 Cov.: 32 AF XY: 0.00336 AC XY: 249 AN XY: 74216

African (AFR) AF: 0.0113 AC: 466 AN: 41386

American (AMR) AF: 0.00295 AC: 45 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67872

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00322 Hom.: 0

Bravo AF: 0.00415

ExAC AF: 0.000756 AC: 21

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	3.8
DANN	Benign	0.92
DEOGEN2	Benign	0.0071	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.024
PrimateAI	Uncertain	0.65	T
Sift4G	Benign	0.60	T
Vest4		0.18
MVP		0.11
ClinPred		0.0025	T
GERP RS		-7.5
gMVP		0.29
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

dbSNP: rs559459711; hg19: chr3-12942625;