Genetic Variant IQSEC1:p.Val1084Met (chr3-12901078-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 11/15 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.31

Publications

0 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

IQSEC1 links:

ENSG00000297478 (HGNC:):

ENSG00000297478 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 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 VariationId is 783367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IQSEC1	NM_001134382.3	MANE Select	c.3250G>A	p.Val1084Met	missense	Exon 14 of 14	NP_001127854.1	Q6DN90-3
IQSEC1	NM_001376938.2		c.3574G>A	p.Val1192Met	missense	Exon 16 of 16	NP_001363867.1	A0A3B3IRZ4
IQSEC1	NM_001330619.3		c.*431G>A		3_prime_UTR	Exon 13 of 13	NP_001317548.1	A0A0C4DGT3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IQSEC1	ENST00000613206.2	TSL:2 MANE Select	c.3250G>A	p.Val1084Met	missense	Exon 14 of 14	ENSP00000480301.1	Q6DN90-3
IQSEC1	ENST00000618604.4	TSL:1	c.*431G>A		3_prime_UTR	Exon 13 of 13	ENSP00000478001.1	A0A0C4DGT3
IQSEC1	ENST00000273221.8	TSL:1	c.2848-1644G>A		intron	N/A	ENSP00000273221.4	Q6DN90-1

Frequencies

GnomAD3 genomes

AF:

0.00615

AC:

922

AN:

150024

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00143

AC:

201

AN:

140820

AF XY:

0.00108

show subpopulations

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 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.:

Cov.:

AF XY:

0.000515

AC XY:

347

AN XY:

673584

show subpopulations

African (AFR)

AF:

0.0208

AC:

641

AN:

30776

American (AMR)

AF:

0.00104

AC:

AN:

34776

Ashkenazi Jewish (ASJ)

AF:

0.0000414

AC:

AN:

24128

East Asian (EAS)

AF:

0.0000291

AC:

AN:

34386

South Asian (SAS)

AF:

0.000114

AC:

AN:

78832

European-Finnish (FIN)

AF:

0.0000270

AC:

AN:

37034

Middle Eastern (MID)

AF:

0.00109

AC:

AN:

5520

European-Non Finnish (NFE)

AF:

0.0000385

AC:

AN:

1063962

Other (OTH)

AF:

0.00107

AC:

AN:

56160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

100

150

200

250

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00615

AC:

923

AN:

150160

Hom.:

Cov.:

AF XY:

0.00560

AC XY:

411

AN XY:

73336

show subpopulations

African (AFR)

AF:

0.0215

AC:

884

AN:

41026

American (AMR)

AF:

0.00152

AC:

AN:

15134

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

4934

South Asian (SAS)

AF:

0.00

AC:

AN:

4586

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10190

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000133

AC:

AN:

67530

Other (OTH)

AF:

0.00333

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

136

181

226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00220

Hom.:

Bravo

AF:

0.00717

ExAC

AF:

0.00188

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.13

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.0071

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0025

MetaSVM

Benign

-1.1

PhyloP100

-1.3

PrimateAI

Uncertain

0.70

Sift4G

Benign

0.23

Vest4

0.18

MVP

0.10

ClinPred

0.0029

GERP RS

-7.4

gMVP

0.18

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over