rs41301291

Positions:

chr1-116584795-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000369486.8(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. 14/20 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
ENST00000369486.8 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.78

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), IGSF3. . Gene score misZ 1.771 (greater than the threshold 3.09). Trascript score misZ 4.0048 (greater than threshold 3.09). GenCC has associacion of gene with familial congenital nasolacrimal duct obstruction.

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 id is 402968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-116584795-C-T is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGSF3	NM_001007237.3 linkuse as main transcript	c.2698G>A	p.Val900Met	missense_variant	9/11	ENST00000369486.8	NP_001007238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGSF3	ENST00000369486.8 linkuse as main transcript	c.2698G>A	p.Val900Met	missense_variant	9/11	1	NM_001007237.3	ENSP00000358498	P4	O75054-1
IGSF3	ENST00000318837.6 linkuse as main transcript	c.2758G>A	p.Val920Met	missense_variant	9/11	2		ENSP00000321184	A1	O75054-2
IGSF3	ENST00000369483.5 linkuse as main transcript	c.2758G>A	p.Val920Met	missense_variant	10/12	5		ENSP00000358495	A1	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

GnomAD3 exomes

AF:

0.0164

AC:

4114

AN:

251430

Hom.:

AF XY:

0.0164

AC XY:

2235

AN XY:

135896

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 SAS exome

AF:

0.00470

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

Gnomad4 AFR exome

AF:

0.00418

Gnomad4 AMR exome

AF:

0.0114

Gnomad4 ASJ exome

AF:

0.0555

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00521

Gnomad4 FIN exome

AF:

0.0330

Gnomad4 NFE exome

AF:

0.0153

Gnomad4 OTH exome

AF:

0.0188

GnomAD4 genome

AF:

0.0137

AC:

2088

AN:

152358

Hom.:

Cov.:

AF XY:

0.0139

AC XY:

1037

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00356

Gnomad4 AMR

AF:

0.0100

Gnomad4 ASJ

AF:

0.0548

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00455

Gnomad4 FIN

AF:

0.0311

Gnomad4 NFE

AF:

0.0172

Gnomad4 OTH

AF:

0.0279

Alfa

AF:

0.0186

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

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

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;.

MutationTaster

Benign

0.97

N;N;N

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over