3-12901002-C-G

Variant names:

• chr3-12901002-C-G
• rs897202413
• NM_001134382.3:c.3326G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001134382.3(IQSEC1):​c.3326G>C​(p.Gly1109Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000615 in 1,545,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1109D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: IQSEC1 NM_001134382.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.57
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09116766).

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.3326G>C	p.Gly1109Ala	missense	Exon 14 of 14	NP_001127854.1	Q6DN90-3
	IQSEC1	NM_001376938.2		c.3650G>C	p.Gly1217Ala	missense	Exon 16 of 16	NP_001363867.1	A0A3B3IRZ4
	IQSEC1	NM_001330619.3		c.*507G>C		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.3326G>C	p.Gly1109Ala	missense	Exon 14 of 14	ENSP00000480301.1	Q6DN90-3
	IQSEC1	ENST00000618604.4	TSL:1	c.*507G>C		3_prime_UTR	Exon 13 of 13	ENSP00000478001.1	A0A0C4DGT3
	IQSEC1	ENST00000273221.8	TSL:1	c.2848-1568G>C		intron	N/A	ENSP00000273221.4	Q6DN90-1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000613 AC: 9 AN: 146920 AF XY: 0.0000509

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000830

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000668 AC: 93 AN: 1392912 Hom.: 0 Cov.: 38 AF XY: 0.0000611 AC XY: 42 AN XY: 687284

African (AFR) AF: 0.00 AC: 0 AN: 31584

American (AMR) AF: 0.00 AC: 0 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25164

East Asian (EAS) AF: 0.00258 AC: 92 AN: 35724

South Asian (SAS) AF: 0.00 AC: 0 AN: 79234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078776

Other (OTH) AF: 0.0000173 AC: 1 AN: 57952

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	22
DANN	Benign	0.77
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-0.93	T
PhyloP100		5.6
PrimateAI	Pathogenic	0.88	D
Sift4G	Benign	0.47	T
Vest4		0.87
MVP		0.18
ClinPred		0.11	T
GERP RS		2.8
gMVP		0.65
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: rs897202413; hg19: chr3-12942501;