NM_001134382.3:c.3066C>T

Variant names:

• chr3-12901262-G-A
• rs571426372
• NM_001134382.3:c.3066C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_001134382.3(IQSEC1):​c.3066C>T​(p.Ala1022Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,540,788 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0023 (10 hom.)
• Consequence: IQSEC1 NM_001134382.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.33
• 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: Labcorp Genetics (formerly Invitae), G2P, 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.

• BP4: Computational evidence support a benign effect (REVEL=0.031).
• BP6: Variant 3-12901262-G-A is Benign according to our data. Variant chr3-12901262-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1176149.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.33 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 10 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.3066C>T	p.Ala1022Ala	synonymous	Exon 14 of 14	NP_001127854.1	Q6DN90-3
	IQSEC1	NM_001376938.2		c.3390C>T	p.Ala1130Ala	synonymous	Exon 16 of 16	NP_001363867.1	A0A3B3IRZ4
	IQSEC1	NM_001330619.3		c.*247C>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.3066C>T	p.Ala1022Ala	synonymous	Exon 14 of 14	ENSP00000480301.1	Q6DN90-3
	IQSEC1	ENST00000618604.4	TSL:1	c.*247C>T		3_prime_UTR	Exon 13 of 13	ENSP00000478001.1	A0A0C4DGT3
	IQSEC1	ENST00000273221.8	TSL:1	c.2847+1511C>T		intron	N/A	ENSP00000273221.4	Q6DN90-1

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 207 AN: 144004 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00155

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00748

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00189

Gnomad OTH AF: 0.000995

GnomAD2 exomes AF: 0.00216 AC: 302 AN: 139818 AF XY: 0.00256

Gnomad AFR exome AF: 0.000190

Gnomad AMR exome AF: 0.000248

Gnomad ASJ exome AF: 0.000737

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000675

Gnomad NFE exome AF: 0.00245

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00225 AC: 3149 AN: 1396662 Hom.: 10 Cov.: 35 AF XY: 0.00239 AC XY: 1647 AN XY: 688858

African (AFR) AF: 0.000350 AC: 11 AN: 31446

American (AMR) AF: 0.000505 AC: 18 AN: 35658

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 27 AN: 25136

East Asian (EAS) AF: 0.0000560 AC: 2 AN: 35732

South Asian (SAS) AF: 0.00620 AC: 491 AN: 79182

European-Finnish (FIN) AF: 0.0000634 AC: 3 AN: 47302

Middle Eastern (MID) AF: 0.00216 AC: 12 AN: 5562

European-Non Finnish (NFE) AF: 0.00229 AC: 2475 AN: 1078704

Other (OTH) AF: 0.00190 AC: 110 AN: 57940

GnomAD4 genome AF: 0.00144 AC: 207 AN: 144126 Hom.: 1 Cov.: 31 AF XY: 0.00150 AC XY: 106 AN XY: 70614

African (AFR) AF: 0.000322 AC: 11 AN: 34164

American (AMR) AF: 0.00155 AC: 23 AN: 14854

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00748 AC: 36 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00189 AC: 128 AN: 67840

Other (OTH) AF: 0.000984 AC: 2 AN: 2032

Alfa AF: 0.00145 Hom.: 0

Bravo AF: 0.00136

ClinVar

ClinVar submissions as Germline

Significance: Likely 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
BayesDel_noAF	Benign	-0.59
CADD	Benign	1.9
DANN	Benign	0.79
PhyloP100		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs571426372; hg19: chr3-12942761;