rs41301291

Variant names:

Variant summary

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

The NM_001007237.3(IGSF3):c.2698G>A(p.Val900Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,614,228 control chromosomes in the GnomAD database, including 267 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 0.014 ( 29 hom., cov: 33)

Exomes 𝑓: 0.016 ( 238 hom. )

Consequence

IGSF3
NM_001007237.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.78

Publications

11 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: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

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=0.0065087676).

BP6

Variant 1-116584795-C-T is Benign according to our data. Variant chr1-116584795-C-T is described in ClinVar as Benign. ClinVar VariationId is 402968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0137 (2088/152358) while in subpopulation NFE AF = 0.0172 (1169/68036). AF 95% confidence interval is 0.0164. There are 29 homozygotes in GnomAd4. There are 1037 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 29 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGSF3	NM_001007237.3 link	c.2698G>A	p.Val900Met	missense_variant	Exon 9 of 11	ENST00000369486.8	NP_001007238.1	O75054-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IGSF3	ENST00000369486.8 link	c.2698G>A	p.Val900Met	missense_variant	Exon 9 of 11	1	NM_001007237.3	ENSP00000358498.4	O75054-1
IGSF3	ENST00000318837.6 link	c.2758G>A	p.Val920Met	missense_variant	Exon 9 of 11	2		ENSP00000321184.6	O75054-2
IGSF3	ENST00000369483.5 link	c.2758G>A	p.Val920Met	missense_variant	Exon 10 of 12	5		ENSP00000358495.1	O75054-2

Frequencies

GnomAD3 genomes

AF:

0.0137

AC:

2091

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00357

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0100

Gnomad ASJ

AF:

0.0548

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00475

Gnomad FIN

AF:

0.0311

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0172

Gnomad OTH

AF:

0.0282

GnomAD2 exomes

AF:

0.0164

AC:

4114

AN:

251430

AF XY:

0.0164

show subpopulations

Gnomad AFR exome

AF:

0.00277

Gnomad AMR exome

AF:

0.0110

Gnomad ASJ exome

AF:

0.0596

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0328

Gnomad NFE exome

AF:

0.0185

Gnomad OTH exome

AF:

0.0202

GnomAD4 exome

AF:

0.0156

AC:

22748

AN:

1461870

Hom.:

238

Cov.:

AF XY:

0.0155

AC XY:

11243

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.00418

AC:

140

AN:

33480

American (AMR)

AF:

0.0114

AC:

509

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0555

AC:

1450

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00521

AC:

449

AN:

86258

European-Finnish (FIN)

AF:

0.0330

AC:

1762

AN:

53420

Middle Eastern (MID)

AF:

0.0499

AC:

287

AN:

5756

European-Non Finnish (NFE)

AF:

0.0153

AC:

17013

AN:

1112004

Other (OTH)

AF:

0.0188

AC:

1138

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

1320

2640

3961

5281

6601

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

636

1272

1908

2544

3180

<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:

0.0137

AC:

2088

AN:

152358

Hom.:

Cov.:

AF XY:

0.0139

AC XY:

1037

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00356

AC:

148

AN:

41586

American (AMR)

AF:

0.0100

AC:

153

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0548

AC:

190

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00455

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0311

AC:

330

AN:

10620

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0172

AC:

1169

AN:

68036

Other (OTH)

AF:

0.0279

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

107

214

320

427

534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0165

Hom.:

Bravo

AF:

0.0126

TwinsUK

AF:

0.0162

AC:

ALSPAC

AF:

0.0140

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0191

AC:

164

ExAC

AF:

0.0159

AC:

1935

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0212

EpiControl

AF:

0.0186

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.024

.;T;.

Eigen

Benign

-0.026

Eigen_PC

Benign

-0.048

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.83

T;T;.

MetaRNN

Benign

0.0065

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

.;N;.

PhyloP100

1.8

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.25

N;N;N

REVEL

Benign

0.21

Sift

Benign

0.21

T;T;T

Sift4G

Benign

0.17

T;T;T

Polyphen

0.99

D;D;D

Vest4

0.26

MPC

1.1

ClinPred

0.016

GERP RS

2.9

Varity_R

0.027

gMVP

0.22

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over