1-116579666-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

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. 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 0.33 (8974 hom., cov: 28)
  • Exomes 𝑓: 0.38 (105070 hom.)
  • Failed GnomAD Quality Control
• Consequence: IGSF3 NM_001007237.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.54

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, IGSF3
• 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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGSF3	NM_001007237.3	c.3060C>G	p.Asp1020Glu	missense_variant	10/11	ENST00000369486.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGSF3	ENST00000369486.8	c.3060C>G	p.Asp1020Glu	missense_variant	10/11	1	NM_001007237.3	P4
IGSF3	ENST00000318837.6	c.3120C>G	p.Asp1040Glu	missense_variant	10/11	2		A1
IGSF3	ENST00000369483.5	c.3120C>G	p.Asp1040Glu	missense_variant	11/12	5		A1

Frequencies

GnomAD3 genomes AF: 0.328 AC: 49109 AN: 149712 Hom.: 8974 Cov.: 28

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

GnomAD3 exomes AF: 0.325 AC: 69863 AN: 215072 Hom.: 12044 AF XY: 0.332 AC XY: 38594 AN XY: 116374

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 SAS exome AF: 0.323

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.: 35 AF XY: 0.377 AC XY: 267864 AN XY: 710572

Gnomad4 AFR exome AF: 0.178

Gnomad4 AMR exome AF: 0.295

Gnomad4 ASJ exome AF: 0.354

Gnomad4 EAS exome AF: 0.128

Gnomad4 SAS exome AF: 0.329

Gnomad4 FIN exome AF: 0.466

Gnomad4 NFE exome AF: 0.397

Gnomad4 OTH exome AF: 0.352

GnomAD4 genome AF: 0.328 AC: 49116 AN: 149828 Hom.: 8974 Cov.: 28 AF XY: 0.330 AC XY: 24130 AN XY: 73054

Gnomad4 AFR AF: 0.181

Gnomad4 AMR AF: 0.338

Gnomad4 ASJ AF: 0.355

Gnomad4 EAS AF: 0.118

Gnomad4 SAS AF: 0.319

Gnomad4 FIN AF: 0.479

Gnomad4 NFE AF: 0.403

Gnomad4 OTH AF: 0.315

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

IGSF3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.0010
Dann	Benign	0.48
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.00092	N
LIST_S2	Benign	0.20	T;T;.
MetaRNN	Benign	0.00019	T;T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.10	N;N;N
REVEL	Benign	0.0070
Sift	Benign	0.74	T;T;T
Sift4G	Benign	0.90	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.15
MutPred		0.21		.;Loss of stability (P = 0.1942);.;
MPC		0.52
ClinPred		0.0038	T
GERP RS		-5.3
Varity_R		0.032
gMVP		0.13

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: rs647711; hg19: chr1-117122288; COSMIC: COSV59586968;