rs137962390

Variant names:

• chr3-12901258-TGGC-T
• rs137962390
• NM_001134382.3:c.3067_3069delGCC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 1P and 10B. PM4_Supporting BP6_Moderate BA1

The NM_001134382.3(IQSEC1):​c.3067_3069delGCC​(p.Ala1023del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00543 in 1,497,386 control chromosomes in the GnomAD database, including 315 homozygotes. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. A1023A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.028 (181 hom., cov: 31)
  • Exomes 𝑓: 0.0030 (134 hom.)
• Consequence: IQSEC1 NM_001134382.3 conservative_inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.33
• 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: Benign. The variant received -9 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001134382.3. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 3-12901258-TGGC-T is Benign according to our data. Variant chr3-12901258-TGGC-T is described in ClinVar as Benign. ClinVar VariationId is 2855636.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0932 is higher than 0.05.

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.3067_3069delGCC	p.Ala1023del	conservative_inframe_deletion	Exon 14 of 14	NP_001127854.1	Q6DN90-3
	IQSEC1	NM_001376938.2		c.3391_3393delGCC	p.Ala1131del	conservative_inframe_deletion	Exon 16 of 16	NP_001363867.1	A0A3B3IRZ4
	IQSEC1	NM_001330619.3		c.*248_*250delGCC		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.3067_3069delGCC	p.Ala1023del	conservative_inframe_deletion	Exon 14 of 14	ENSP00000480301.1	Q6DN90-3
	IQSEC1	ENST00000618604.4	TSL:1	c.*248_*250delGCC		3_prime_UTR	Exon 13 of 13	ENSP00000478001.1	A0A0C4DGT3
	IQSEC1	ENST00000273221.8	TSL:1	c.2847+1512_2847+1514delGCC		intron	N/A	ENSP00000273221.4	Q6DN90-1

Frequencies

GnomAD3 genomes AF: 0.0279 AC: 4097 AN: 146828 Hom.: 180 Cov.: 31

Gnomad AFR AF: 0.0960

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000676

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00649

Gnomad NFE AF: 0.000597

Gnomad OTH AF: 0.0202

GnomAD2 exomes AF: 0.00544 AC: 769 AN: 141388 AF XY: 0.00471

Gnomad AFR exome AF: 0.0970

Gnomad AMR exome AF: 0.00409

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000498

Gnomad OTH exome AF: 0.00242

GnomAD4 exome AF: 0.00299 AC: 4034 AN: 1350470 Hom.: 134 AF XY: 0.00254 AC XY: 1694 AN XY: 665914

African (AFR) AF: 0.102 AC: 3100 AN: 30276

American (AMR) AF: 0.00500 AC: 171 AN: 34212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23270

East Asian (EAS) AF: 0.0000315 AC: 1 AN: 31784

South Asian (SAS) AF: 0.000356 AC: 28 AN: 78762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41796

Middle Eastern (MID) AF: 0.00531 AC: 28 AN: 5278

European-Non Finnish (NFE) AF: 0.000318 AC: 334 AN: 1050434

Other (OTH) AF: 0.00681 AC: 372 AN: 54658

GnomAD4 genome AF: 0.0279 AC: 4096 AN: 146916 Hom.: 181 Cov.: 31 AF XY: 0.0269 AC XY: 1924 AN XY: 71554

African (AFR) AF: 0.0957 AC: 3794 AN: 39638

American (AMR) AF: 0.0148 AC: 217 AN: 14710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3446

East Asian (EAS) AF: 0.00 AC: 0 AN: 4692

South Asian (SAS) AF: 0.000451 AC: 2 AN: 4430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9728

Middle Eastern (MID) AF: 0.00699 AC: 2 AN: 286

European-Non Finnish (NFE) AF: 0.000597 AC: 40 AN: 67038

Other (OTH) AF: 0.0200 AC: 41 AN: 2048

Alfa AF: 0.0159 Hom.: 20

Bravo AF: 0.0316

Asia WGS AF: 0.00462 AC: 18 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
PhyloP100		2.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs137962390; hg19: chr3-12942757;