3-12901126-C-T

Variant summary

Our verdict is Benign. Variant got -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. 9/12 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

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]

LOC105376956 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 710916.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQSEC1	NM_001134382.3	c.3202G>A	p.Ala1068Thr	missense_variant	14/14	ENST00000613206.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQSEC1	ENST00000613206.2	c.3202G>A	p.Ala1068Thr	missense_variant	14/14	2	NM_001134382.3

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

GnomAD3 exomes AF: 0.000740 AC: 104 AN: 140482 Hom.: 0 AF XY: 0.000606 AC XY: 46 AN XY: 75910

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 SAS 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

Gnomad4 AFR exome AF: 0.0136

Gnomad4 AMR exome AF: 0.000845

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000506

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000195

Gnomad4 OTH exome AF: 0.000778

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

Gnomad4 AFR AF: 0.0113

Gnomad4 AMR AF: 0.00295

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000989 Hom.: 0

Bravo AF: 0.00415

ExAC AF: 0.000756 AC: 21

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	3.8
Dann	Benign	0.92
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.69	T;T
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.65	T
Vest4		0.18
MVP		0.11
ClinPred		0.0025	T
GERP RS		-7.5
gMVP		0.29

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

Publications

LitVar

Other links and lift over

dbSNP: rs559459711; hg19: chr3-12942625;