NM_001007237.3:c.3218A>G

Variant names:

• chr1-116579508-T-C
• rs6703791
• NM_001007237.3:c.3218A>G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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 (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in 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 no assertion criteria provided 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.

• 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 no_assertion_criteria_provided, 0 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 rank	MANE	Protein	UniProt
IGSF3	NM_001007237.3	c.3218A>G	p.Gln1073Arg	missense_variant	Exon 10 of 11	ENST00000369486.8	NP_001007238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGSF3	ENST00000369486.8	c.3218A>G	p.Gln1073Arg	missense_variant	Exon 10 of 11	1	NM_001007237.3	ENSP00000358498.4
IGSF3	ENST00000318837.6	c.3278A>G	p.Gln1093Arg	missense_variant	Exon 10 of 11	2		ENSP00000321184.6
IGSF3	ENST00000369483.5	c.3278A>G	p.Gln1093Arg	missense_variant	Exon 11 of 12	5		ENSP00000358495.1

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: no assertion criteria provided

Submissions by phenotype

IGSF3-related disorder Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
DEOGEN2	Benign	0.012	.;T;.
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
MutationAssessor	Benign	0.90	.;L;.
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;