rs11128623

Variant names:

• chr3-12898330-T-C
• rs11128623
• NM_001134382.3:c.*2653A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001134382.3(IQSEC1):​c.*2653A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0811 in 152,320 control chromosomes in the GnomAD database, including 1,028 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.081 (1028 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IQSEC1 NM_001134382.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.295
• Publications: 5 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000297478 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.21 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.*2653A>G		3_prime_UTR	Exon 14 of 14	NP_001127854.1
	IQSEC1	NM_001376938.2		c.*2653A>G		3_prime_UTR	Exon 16 of 16	NP_001363867.1
	IQSEC1	NM_014869.8		c.*1060A>G		3_prime_UTR	Exon 14 of 14	NP_055684.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC1	ENST00000613206.2	TSL:2 MANE Select	c.*2653A>G		3_prime_UTR	Exon 14 of 14	ENSP00000480301.1
	IQSEC1	ENST00000273221.8	TSL:1	c.*1060A>G		3_prime_UTR	Exon 14 of 14	ENSP00000273221.4
	IQSEC1	ENST00000646269.1		c.*1060A>G		3_prime_UTR	Exon 14 of 14	ENSP00000496366.1

Frequencies

GnomAD3 genomes AF: 0.0809 AC: 12311 AN: 152202 Hom.: 1015 Cov.: 33

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0440

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.0286

Gnomad SAS AF: 0.0281

Gnomad FIN AF: 0.0239

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0301

Gnomad OTH AF: 0.0611

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 18 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 12

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 10

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0811 AC: 12352 AN: 152320 Hom.: 1028 Cov.: 33 AF XY: 0.0803 AC XY: 5983 AN XY: 74500

African (AFR) AF: 0.214 AC: 8887 AN: 41546

American (AMR) AF: 0.0438 AC: 671 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3472

East Asian (EAS) AF: 0.0287 AC: 149 AN: 5192

South Asian (SAS) AF: 0.0280 AC: 135 AN: 4830

European-Finnish (FIN) AF: 0.0239 AC: 254 AN: 10626

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0301 AC: 2048 AN: 68026

Other (OTH) AF: 0.0605 AC: 128 AN: 2116

Alfa AF: 0.0448 Hom.: 498

Bravo AF: 0.0888

Asia WGS AF: 0.0410 AC: 143 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.80
DANN	Benign	0.72
PhyloP100		0.29
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: rs11128623; hg19: chr3-12939829;