1-116579508-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BA1

The NM_001007237.3(IGSF3):c.3218A>G(p.Gln1073Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,613,634 control chromosomes in the GnomAD database, including 42,457 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.25 (5406 hom., cov: 31)
  • Exomes 𝑓: 0.21 (37051 hom.)
• Consequence: IGSF3 NM_001007237.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.269

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, IGSF3
• BP4: Computational evidence support a benign effect (MetaRNN=1.0800014E-4).
• BP6: Variant 1-116579508-T-C is Benign according to our data. Variant chr1-116579508-T-C is described in ClinVar as [Benign]. Clinvar id is 3061000.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.497 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGSF3	NM_001007237.3	c.3218A>G	p.Gln1073Arg	missense_variant	10/11	ENST00000369486.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGSF3	ENST00000369486.8	c.3218A>G	p.Gln1073Arg	missense_variant	10/11	1	NM_001007237.3	P4
IGSF3	ENST00000318837.6	c.3278A>G	p.Gln1093Arg	missense_variant	10/11	2		A1
IGSF3	ENST00000369483.5	c.3278A>G	p.Gln1093Arg	missense_variant	11/12	5		A1

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37600 AN: 151768 Hom.: 5389 Cov.: 31

Gnomad AFR AF: 0.349

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.514

Gnomad SAS AF: 0.357

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.228

GnomAD3 exomes AF: 0.258 AC: 64687 AN: 251060 Hom.: 10206 AF XY: 0.252 AC XY: 34163 AN XY: 135790

Gnomad AFR exome AF: 0.351

Gnomad AMR exome AF: 0.375

Gnomad ASJ exome AF: 0.170

Gnomad EAS exome AF: 0.517

Gnomad SAS exome AF: 0.346

Gnomad FIN exome AF: 0.125

Gnomad NFE exome AF: 0.178

Gnomad OTH exome AF: 0.210

GnomAD4 exome AF: 0.208 AC: 303412 AN: 1461748 Hom.: 37051 Cov.: 35 AF XY: 0.210 AC XY: 152610 AN XY: 727180

Gnomad4 AFR exome AF: 0.354

Gnomad4 AMR exome AF: 0.362

Gnomad4 ASJ exome AF: 0.171

Gnomad4 EAS exome AF: 0.556

Gnomad4 SAS exome AF: 0.340

Gnomad4 FIN exome AF: 0.127

Gnomad4 NFE exome AF: 0.178

Gnomad4 OTH exome AF: 0.217

GnomAD4 genome AF: 0.248 AC: 37662 AN: 151886 Hom.: 5406 Cov.: 31 AF XY: 0.249 AC XY: 18502 AN XY: 74228

Gnomad4 AFR AF: 0.349

Gnomad4 AMR AF: 0.283

Gnomad4 ASJ AF: 0.161

Gnomad4 EAS AF: 0.513

Gnomad4 SAS AF: 0.359

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.176

Gnomad4 OTH AF: 0.230

Alfa AF: 0.199 Hom.: 8627

Bravo AF: 0.267

TwinsUK AF: 0.186 AC: 689

ALSPAC AF: 0.190 AC: 731

ESP6500AA AF: 0.353 AC: 1555

ESP6500EA AF: 0.181 AC: 1560

ExAC AF: 0.257 AC: 31161

Asia WGS AF: 0.439 AC: 1525 AN: 3478

EpiCase AF: 0.175

EpiControl AF: 0.178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

IGSF3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.039
Dann	Benign	0.22
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.069	T;T;.
MetaRNN	Benign	0.00011	T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.010	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.86	T;T;T
Sift4G	Benign	0.52	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.051
MPC		0.60
ClinPred		0.00041	T
GERP RS		-4.5
Varity_R		0.036
gMVP		0.22

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

LitVar

Other links and lift over

dbSNP: rs6703791; hg19: chr1-117122130; COSMIC: COSV59586434;