Genetic Variant NM_001170738.2:c.41A>G (chr12-66923-A-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM2BP4_StrongBP6_Very_Strong

The NM_001170738.2(IQSEC3):c.41A>G(p.Tyr14Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00233 in 1,435,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 0 hom. )

Consequence

IQSEC3
NM_001170738.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.12

Publications

3 publications found

Variant links:

Genes affected

IQSEC3 (HGNC:29193): (IQ motif and Sec7 domain ArfGEF 3) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in several processes, including actin cytoskeleton organization; activation of GTPase activity; and regulation of small GTPase mediated signal transduction. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

IQSEC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM2

Variant has high frequency in the MID (0.00379) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).

BP4

Computational evidence support a benign effect (MetaRNN=0.054054618).

BP6

Variant 12-66923-A-G is Benign according to our data. Variant chr12-66923-A-G is described in ClinVar as [Benign]. Clinvar id is 778075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQSEC3	NM_001170738.2 link	c.41A>G	p.Tyr14Cys	missense_variant	Exon 1 of 14	ENST00000538872.6	NP_001164209.1	Q9UPP2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQSEC3	ENST00000538872.6 link	c.41A>G	p.Tyr14Cys	missense_variant	Exon 1 of 14	5	NM_001170738.2	ENSP00000437554.1		Q9UPP2-1

Frequencies

GnomAD3 genomes

AF:

0.00238

AC:

356

AN:

149542

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000880

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00126

Gnomad ASJ

AF:

0.00263

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.00128

Gnomad FIN

AF:

0.000389

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00417

Gnomad OTH

AF:

0.00146

GnomAD2 exomes

AF:

0.00204

AC:

229

AN:

112516

AF XY:

0.00215

show subpopulations

Gnomad AFR exome

AF:

0.00273

Gnomad AMR exome

AF:

0.00148

Gnomad ASJ exome

AF:

0.00168

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00124

Gnomad NFE exome

AF:

0.00339

Gnomad OTH exome

AF:

0.00273

GnomAD4 exome

AF:

0.00233

AC:

2990

AN:

1285458

Hom.:

Cov.:

AF XY:

0.00259

AC XY:

1636

AN XY:

631852

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000539

AC:

AN:

27814

American (AMR)

AF:

0.00265

AC:

AN:

31000

Ashkenazi Jewish (ASJ)

AF:

0.00479

AC:

108

AN:

22554

East Asian (EAS)

AF:

0.0000915

AC:

AN:

32796

South Asian (SAS)

AF:

0.00421

AC:

267

AN:

63446

European-Finnish (FIN)

AF:

0.00143

AC:

AN:

30136

Middle Eastern (MID)

AF:

0.00459

AC:

AN:

4792

European-Non Finnish (NFE)

AF:

0.00224

AC:

2282

AN:

1019702

Other (OTH)

AF:

0.00316

AC:

168

AN:

53218

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.288

Heterozygous variant carriers

231

461

692

922

1153

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00238

AC:

356

AN:

149652

Hom.:

Cov.:

AF XY:

0.00193

AC XY:

141

AN XY:

73116

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000878

AC:

AN:

41024

American (AMR)

AF:

0.00126

AC:

AN:

15138

Ashkenazi Jewish (ASJ)

AF:

0.00263

AC:

AN:

3418

East Asian (EAS)

AF:

0.000196

AC:

AN:

5106

South Asian (SAS)

AF:

0.00128

AC:

AN:

4692

European-Finnish (FIN)

AF:

0.000389

AC:

AN:

10290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00417

AC:

278

AN:

66712

Other (OTH)

AF:

0.00144

AC:

AN:

2080

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.261

Heterozygous variant carriers

127

170

212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00508

Hom.:

ExAC

AF:

0.000493

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 22, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.043

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.063

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.20

FATHMM_MKL

Benign

0.12

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.054

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

PhyloP100

5.1

PrimateAI

Pathogenic

0.96

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.30

Sift

Uncertain

0.016

Sift4G

Pathogenic

0.0010

Vest4

0.72

MVP

0.60

MPC

3.5

ClinPred

0.053

GERP RS

3.7

PromoterAI

-0.0038

Neutral

(source)

Varity_R

0.30

gMVP

0.77

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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NM_001170738.2:c.41A>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over