1-116579663-G-C

Variant names:

• chr1-116579663-G-C
• rs114915440
• NM_001007237.3:c.3063C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 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 0.0052 (10 hom., cov: 28)
  • Exomes 𝑓: 0.0037 (18 hom.)
• Consequence: IGSF3 NM_001007237.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.34
• Publications: 13 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: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• 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 VariationId is 3041771.Status of the report is no_assertion_criteria_provided, 0 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 the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR,Unknown gene

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.3063C>G	p.Asp1021Glu	missense	Exon 10 of 11	NP_001007238.1	O75054-1
	IGSF3	NM_001542.4		c.3123C>G	p.Asp1041Glu	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.3063C>G	p.Asp1021Glu	missense	Exon 10 of 11	ENSP00000358498.4	O75054-1
	IGSF3	ENST00000318837.6	TSL:2	c.3123C>G	p.Asp1041Glu	missense	Exon 10 of 11	ENSP00000321184.6	O75054-2
	IGSF3	ENST00000369483.5	TSL:5	c.3123C>G	p.Asp1041Glu	missense	Exon 11 of 12	ENSP00000358495.1	O75054-2

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

GnomAD2 exomes AF: 0.00726 AC: 1555 AN: 214242 AF XY: 0.00679

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 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

African (AFR) AF: 0.000428 AC: 14 AN: 32690

American (AMR) AF: 0.0211 AC: 912 AN: 43268

Ashkenazi Jewish (ASJ) AF: 0.000236 AC: 6 AN: 25466

East Asian (EAS) AF: 0.000228 AC: 9 AN: 39488

South Asian (SAS) AF: 0.00340 AC: 285 AN: 83722

European-Finnish (FIN) AF: 0.0193 AC: 974 AN: 50584

Middle Eastern (MID) AF: 0.00211 AC: 12 AN: 5692

European-Non Finnish (NFE) AF: 0.00260 AC: 2793 AN: 1074048

Other (OTH) AF: 0.00329 AC: 193 AN: 58598

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

African (AFR) AF: 0.000682 AC: 28 AN: 41054

American (AMR) AF: 0.0204 AC: 309 AN: 15150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00484 AC: 23 AN: 4748

European-Finnish (FIN) AF: 0.0191 AC: 197 AN: 10300

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.00309 AC: 208 AN: 67374

Other (OTH) AF: 0.00864 AC: 18 AN: 2084

Alfa AF: 0.00188 Hom.: 0

ExAC AF: 0.00583 AC: 706

ClinVar

ClinVar submissions

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	0.068
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.023
DANN	Benign	0.18
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.17	N
PhyloP100		-1.3
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.24	N
REVEL	Benign	0.015
Sift	Benign	1.0	T
Sift4G	Benign	0.78	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
Mutation Taster		=100/0	polymorphism

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