3-12901261-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001134382.3(IQSEC1):c.3067G>C(p.Ala1023Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00637 in 1,530,954 control chromosomes in the GnomAD database, including 63 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 (★). Synonymous variant affecting the same amino acid position (i.e. A1023A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (29 hom., cov: 31)
  • Exomes 𝑓: 0.0057 (34 hom.)
• Consequence: IQSEC1 NM_001134382.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.33

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031626523).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0134 (1914/143076) while in subpopulation AFR AF= 0.0417 (1417/33990). AF 95% confidence interval is 0.0399. There are 29 homozygotes in gnomad4. There are 876 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQSEC1	NM_001134382.3	c.3067G>C	p.Ala1023Pro	missense_variant	14/14	ENST00000613206.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQSEC1	ENST00000613206.2	c.3067G>C	p.Ala1023Pro	missense_variant	14/14	2	NM_001134382.3

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 1897 AN: 142960 Hom.: 27 Cov.: 31

Gnomad AFR AF: 0.0414

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00761

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000424

Gnomad FIN AF: 0.00222

Gnomad MID AF: 0.00325

Gnomad NFE AF: 0.00494

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00452 AC: 637 AN: 141068 Hom.: 0 AF XY: 0.00400 AC XY: 306 AN XY: 76506

Gnomad AFR exome AF: 0.0357

Gnomad AMR exome AF: 0.00463

Gnomad ASJ exome AF: 0.000491

Gnomad EAS exome AF: 0.000280

Gnomad SAS exome AF: 0.000312

Gnomad FIN exome AF: 0.00156

Gnomad NFE exome AF: 0.00474

Gnomad OTH exome AF: 0.00461

GnomAD4 exome AF: 0.00565 AC: 7843 AN: 1387878 Hom.: 34 Cov.: 35 AF XY: 0.00532 AC XY: 3647 AN XY: 685024

Gnomad4 AFR exome AF: 0.0414

Gnomad4 AMR exome AF: 0.00482

Gnomad4 ASJ exome AF: 0.000518

Gnomad4 EAS exome AF: 0.000140

Gnomad4 SAS exome AF: 0.000253

Gnomad4 FIN exome AF: 0.00159

Gnomad4 NFE exome AF: 0.00556

Gnomad4 OTH exome AF: 0.00823

GnomAD4 genome AF: 0.0134 AC: 1914 AN: 143076 Hom.: 29 Cov.: 31 AF XY: 0.0125 AC XY: 876 AN XY: 69992

Gnomad4 AFR AF: 0.0417

Gnomad4 AMR AF: 0.00759

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000424

Gnomad4 FIN AF: 0.00222

Gnomad4 NFE AF: 0.00494

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.000366 Hom.: 0

Bravo AF: 0.0144

ExAC AF: 0.00216 AC: 55

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	-0.57	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	9.7
Dann	Benign	0.46
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.36	T;T
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
Vest4		0.16
MVP		0.082
ClinPred		0.0022	T
GERP RS		3.1
gMVP		0.44

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: rs185165059; hg19: chr3-12942760;