Genetic Variant IGSF3:p.Asp1020Glu (chr1-116579666-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001007237.3(IGSF3):c.3060C>G(p.Asp1020Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 149,828 control chromosomes in the GnomAD database, including 8,974 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 8974 hom., cov: 28)

Exomes 𝑓: 0.38 ( 105070 hom. )

Failed GnomAD Quality Control

Consequence

IGSF3
NM_001007237.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -3.54

Publications

25 publications found

Variant links:

Genes affected

IGSF3 (HGNC:5950): (immunoglobulin superfamily member 3) The protein encoded by this gene is an immunoglobulin-like membrane protein containing several V-type Ig-like domains. A mutation in this gene has been associated with bilateral nasolacrimal duct obstruction (LCDD). [provided by RefSeq, Jun 2016]

IGSF3 Gene-Disease associations (from GenCC):

familial congenital nasolacrimal duct obstruction
Inheritance: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

IGSF3 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=1.8504262E-4).

BP6

Variant 1-116579666-G-C is Benign according to our data. Variant chr1-116579666-G-C is described in ClinVar as Benign. ClinVar VariationId is 769242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.399 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001007237.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGSF3	NM_001007237.3	MANE Select	c.3060C>G	p.Asp1020Glu	missense	Exon 10 of 11	NP_001007238.1	O75054-1
	IGSF3	NM_001542.4		c.3120C>G	p.Asp1040Glu	missense	Exon 11 of 12	NP_001533.2	O75054-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IGSF3	ENST00000369486.8	TSL:1 MANE Select	c.3060C>G	p.Asp1020Glu	missense	Exon 10 of 11	ENSP00000358498.4	O75054-1
IGSF3	ENST00000318837.6	TSL:2	c.3120C>G	p.Asp1040Glu	missense	Exon 10 of 11	ENSP00000321184.6	O75054-2
IGSF3	ENST00000369483.5	TSL:5	c.3120C>G	p.Asp1040Glu	missense	Exon 11 of 12	ENSP00000358495.1	O75054-2

Frequencies

GnomAD3 genomes

AF:

0.328

AC:

49109

AN:

149712

Hom.:

8974

Cov.:

show subpopulations

Gnomad AFR

AF:

0.181

Gnomad AMI

AF:

0.666

Gnomad AMR

AF:

0.339

Gnomad ASJ

AF:

0.355

Gnomad EAS

AF:

0.118

Gnomad SAS

AF:

0.319

Gnomad FIN

AF:

0.479

Gnomad MID

AF:

0.292

Gnomad NFE

AF:

0.403

Gnomad OTH

AF:

0.319

GnomAD2 exomes

AF:

0.325

AC:

69863

AN:

215072

AF XY:

0.332

show subpopulations

Gnomad AFR exome

AF:

0.151

Gnomad AMR exome

AF:

0.291

Gnomad ASJ exome

AF:

0.346

Gnomad EAS exome

AF:

0.125

Gnomad FIN exome

AF:

0.458

Gnomad NFE exome

AF:

0.370

Gnomad OTH exome

AF:

0.346

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.377

AC:

539225

AN:

1429598

Hom.:

105070

Cov.:

AF XY:

0.377

AC XY:

267864

AN XY:

710572

show subpopulations

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

African (AFR)

AF:

0.178

AC:

5814

AN:

32580

American (AMR)

AF:

0.295

AC:

12644

AN:

42844

Ashkenazi Jewish (ASJ)

AF:

0.354

AC:

9092

AN:

25704

East Asian (EAS)

AF:

0.128

AC:

5019

AN:

39146

South Asian (SAS)

AF:

0.329

AC:

27706

AN:

84146

European-Finnish (FIN)

AF:

0.466

AC:

23820

AN:

51144

Middle Eastern (MID)

AF:

0.297

AC:

1689

AN:

5690

European-Non Finnish (NFE)

AF:

0.397

AC:

432613

AN:

1089210

Other (OTH)

AF:

0.352

AC:

20828

AN:

59134

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.398

Heterozygous variant carriers

16892

33784

50677

67569

84461

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13138

26276

39414

52552

65690

<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:

0.328

AC:

49116

AN:

149828

Hom.:

8974

Cov.:

AF XY:

0.330

AC XY:

24130

AN XY:

73054

show subpopulations

African (AFR)

AF:

0.181

AC:

7393

AN:

40804

American (AMR)

AF:

0.338

AC:

5114

AN:

15118

Ashkenazi Jewish (ASJ)

AF:

0.355

AC:

1224

AN:

3448

East Asian (EAS)

AF:

0.118

AC:

605

AN:

5114

South Asian (SAS)

AF:

0.319

AC:

1503

AN:

4714

European-Finnish (FIN)

AF:

0.479

AC:

4876

AN:

10176

Middle Eastern (MID)

AF:

0.295

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.403

AC:

27071

AN:

67200

Other (OTH)

AF:

0.315

AC:

655

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

1416

2832

4248

5664

7080

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

480

960

1440

1920

2400

<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:

0.345

Hom.:

2909

Bravo

AF:

0.311

ESP6500AA

AF:

0.134

AC:

592

ESP6500EA

AF:

0.288

AC:

2480

ExAC

AF:

0.322

AC:

38994

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

IGSF3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.0010

(source)

DANN

Benign

0.48

DEOGEN2

Benign

0.013

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.00092

LIST_S2

Benign

0.20

MetaRNN

Benign

0.00019

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-0.20

PhyloP100

-3.5

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.10

REVEL

Benign

0.0070

Sift

Benign

0.74

Sift4G

Benign

0.90

Polyphen

0.0

Vest4

0.15

MutPred

0.21

Loss of stability (P = 0.1942)

MPC

0.52

ClinPred

0.0038

GERP RS

-5.3

Varity_R

0.032

gMVP

0.13

Mutation Taster

=100/0

polymorphism (auto)

(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