3-12901078-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001134382.3(IQSEC1):c.3250G>A(p.Val1084Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,515,734 control chromosomes in the GnomAD database, including 15 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 0.0061 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (4 hom.)
• Consequence: IQSEC1 NM_001134382.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.31

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002505958).
• BP6: Variant 3-12901078-C-T is Benign according to our data. Variant chr3-12901078-C-T is described in ClinVar as [Benign]. Clinvar id is 783367.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-12901078-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00615 (923/150160) while in subpopulation AFR AF= 0.0215 (884/41026). AF 95% confidence interval is 0.0204. There are 11 homozygotes in gnomad4. There are 411 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQSEC1	NM_001134382.3	c.3250G>A	p.Val1084Met	missense_variant	14/14	ENST00000613206.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQSEC1	ENST00000613206.2	c.3250G>A	p.Val1084Met	missense_variant	14/14	2	NM_001134382.3

Frequencies

GnomAD3 genomes AF: 0.00615 AC: 922 AN: 150024 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0216

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00152

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: 0.000133

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00143 AC: 201 AN: 140820 Hom.: 1 AF XY: 0.00108 AC XY: 82 AN XY: 75806

Gnomad AFR exome AF: 0.0239

Gnomad AMR exome AF: 0.000863

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000445

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000554

Gnomad OTH exome AF: 0.000722

GnomAD4 exome AF: 0.000583 AC: 796 AN: 1365574 Hom.: 4 Cov.: 37 AF XY: 0.000515 AC XY: 347 AN XY: 673584

Gnomad4 AFR exome AF: 0.0208

Gnomad4 AMR exome AF: 0.00104

Gnomad4 ASJ exome AF: 0.0000414

Gnomad4 EAS exome AF: 0.0000291

Gnomad4 SAS exome AF: 0.000114

Gnomad4 FIN exome AF: 0.0000270

Gnomad4 NFE exome AF: 0.0000385

Gnomad4 OTH exome AF: 0.00107

GnomAD4 genome AF: 0.00615 AC: 923 AN: 150160 Hom.: 11 Cov.: 32 AF XY: 0.00560 AC XY: 411 AN XY: 73336

Gnomad4 AFR AF: 0.0215

Gnomad4 AMR AF: 0.00152

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000133

Gnomad4 OTH AF: 0.00333

Alfa AF: 0.00220 Hom.: 1

Bravo AF: 0.00717

ExAC AF: 0.00188 AC: 59

Asia WGS AF: 0.00144 AC: 5 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

Jul 16, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	0.13
Dann	Benign	0.85
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.57	T;T
MetaRNN	Benign	0.0025	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.68	D
PrimateAI	Uncertain	0.70	T
Vest4		0.18
MVP		0.10
ClinPred		0.0029	T
GERP RS		-7.4
gMVP		0.18

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: rs199524243; hg19: chr3-12942577;