1-116579508-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• 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
• Publications: 38 publications found

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 Gene-Disease associations (from GenCC):

• familial congenital nasolacrimal duct obstruction

  Inheritance: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001007237.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGSF3	NM_001007237.3	MANE Select	c.3218A>G	p.Gln1073Arg	missense	Exon 10 of 11	NP_001007238.1	O75054-1
	IGSF3	NM_001542.4		c.3278A>G	p.Gln1093Arg	missense	Exon 11 of 12	NP_001533.2	O75054-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGSF3	ENST00000369486.8	TSL:1 MANE Select	c.3218A>G	p.Gln1073Arg	missense	Exon 10 of 11	ENSP00000358498.4	O75054-1
	IGSF3	ENST00000318837.6	TSL:2	c.3278A>G	p.Gln1093Arg	missense	Exon 10 of 11	ENSP00000321184.6	O75054-2
	IGSF3	ENST00000369483.5	TSL:5	c.3278A>G	p.Gln1093Arg	missense	Exon 11 of 12	ENSP00000358495.1	O75054-2

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

GnomAD2 exomes AF: 0.258 AC: 64687 AN: 251060 AF XY: 0.252

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 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

African (AFR) AF: 0.354 AC: 11837 AN: 33478

American (AMR) AF: 0.362 AC: 16193 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 4475 AN: 26134

East Asian (EAS) AF: 0.556 AC: 22077 AN: 39700

South Asian (SAS) AF: 0.340 AC: 29302 AN: 86252

European-Finnish (FIN) AF: 0.127 AC: 6751 AN: 53338

Middle Eastern (MID) AF: 0.202 AC: 1167 AN: 5768

European-Non Finnish (NFE) AF: 0.178 AC: 198480 AN: 1111970

Other (OTH) AF: 0.217 AC: 13130 AN: 60390

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

African (AFR) AF: 0.349 AC: 14464 AN: 41388

American (AMR) AF: 0.283 AC: 4326 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 556 AN: 3464

East Asian (EAS) AF: 0.513 AC: 2627 AN: 5118

South Asian (SAS) AF: 0.359 AC: 1720 AN: 4796

European-Finnish (FIN) AF: 0.126 AC: 1333 AN: 10602

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.176 AC: 11987 AN: 67930

Other (OTH) AF: 0.230 AC: 483 AN: 2102

Alfa AF: 0.207 Hom.: 13167

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

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	IGSF3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.00011	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.27
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.12
Sift	Benign	0.86	T
Sift4G	Benign	0.52	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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

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