1-116579663-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_001007237.3(IGSF3):c.3063C>G(p.Asp1021Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00383 in 1,564,050 control chromosomes in the GnomAD database, including 28 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 0.0052 (10 hom., cov: 28)
  • Exomes 𝑓: 0.0037 (18 hom.)
• Consequence: IGSF3 NM_001007237.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.34

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=0.007328391).
• BP6: Variant 1-116579663-G-C is Benign according to our data. Variant chr1-116579663-G-C is described in ClinVar as [Benign]. Clinvar id is 3041771.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00525 (790/150494) while in subpopulation AMR AF= 0.0204 (309/15150). AF 95% confidence interval is 0.0185. There are 10 homozygotes in gnomad4. There are 465 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGSF3	NM_001007237.3	c.3063C>G	p.Asp1021Glu	missense_variant	10/11	ENST00000369486.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGSF3	ENST00000369486.8	c.3063C>G	p.Asp1021Glu	missense_variant	10/11	1	NM_001007237.3	P4
IGSF3	ENST00000318837.6	c.3123C>G	p.Asp1041Glu	missense_variant	10/11	2		A1
IGSF3	ENST00000369483.5	c.3123C>G	p.Asp1041Glu	missense_variant	11/12	5		A1

Frequencies

GnomAD3 genomes AF: 0.00525 AC: 790 AN: 150376 Hom.: 10 Cov.: 28

Gnomad AFR AF: 0.000684

Gnomad AMI AF: 0.00680

Gnomad AMR AF: 0.0204

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00484

Gnomad FIN AF: 0.0191

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.00309

Gnomad OTH AF: 0.00873

GnomAD3 exomes AF: 0.00726 AC: 1555 AN: 214242 Hom.: 12 AF XY: 0.00679 AC XY: 785 AN XY: 115596

Gnomad AFR exome AF: 0.000411

Gnomad AMR exome AF: 0.0220

Gnomad ASJ exome AF: 0.000338

Gnomad EAS exome AF: 0.000171

Gnomad SAS exome AF: 0.00333

Gnomad FIN exome AF: 0.0211

Gnomad NFE exome AF: 0.00385

Gnomad OTH exome AF: 0.00604

GnomAD4 exome AF: 0.00368 AC: 5198 AN: 1413556 Hom.: 18 Cov.: 40 AF XY: 0.00362 AC XY: 2542 AN XY: 702966

Gnomad4 AFR exome AF: 0.000428

Gnomad4 AMR exome AF: 0.0211

Gnomad4 ASJ exome AF: 0.000236

Gnomad4 EAS exome AF: 0.000228

Gnomad4 SAS exome AF: 0.00340

Gnomad4 FIN exome AF: 0.0193

Gnomad4 NFE exome AF: 0.00260

Gnomad4 OTH exome AF: 0.00329

GnomAD4 genome AF: 0.00525 AC: 790 AN: 150494 Hom.: 10 Cov.: 28 AF XY: 0.00633 AC XY: 465 AN XY: 73486

Gnomad4 AFR AF: 0.000682

Gnomad4 AMR AF: 0.0204

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00484

Gnomad4 FIN AF: 0.0191

Gnomad4 NFE AF: 0.00309

Gnomad4 OTH AF: 0.00864

Alfa AF: 0.00188 Hom.: 0

ExAC AF: 0.00583 AC: 706

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

Sep 26, 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	0.068
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.023
Dann	Benign	0.18
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.19	T;T;.
MetaRNN	Benign	0.0073	T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.24	N;N;N
REVEL	Benign	0.015
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.78	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.077
MutPred		0.27		.;Loss of stability (P = 0.2926);.;
MVP		0.068
MPC		0.52
ClinPred		0.0017	T
GERP RS		0.33
Varity_R		0.046
gMVP		0.16

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: rs114915440; hg19: chr1-117122285; COSMIC: COSV59589134;