chr1-116579662-CG-C

Variant names:

• chr1-116579662-CG-C
• rs766373978
• NM_001007237.3:c.3063delC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001007237.3(IGSF3):​c.3063delC​(p.Asp1021GlufsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000212 in 1,592,098 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: IGSF3 NM_001007237.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -1.34
• Publications: 0 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 1-116579662-CG-C is Pathogenic according to our data. Variant chr1-116579662-CG-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1678181.Status of the report is criteria_provided_single_submitter, 1 stars.

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.3063delC	p.Asp1021GlufsTer14	frameshift	Exon 10 of 11	NP_001007238.1	O75054-1
	IGSF3	NM_001542.4		c.3123delC	p.Asp1041GlufsTer14	frameshift	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.3063delC	p.Asp1021GlufsTer14	frameshift	Exon 10 of 11	ENSP00000358498.4	O75054-1
	IGSF3	ENST00000318837.6	TSL:2	c.3123delC	p.Asp1041GlufsTer14	frameshift	Exon 10 of 11	ENSP00000321184.6	O75054-2
	IGSF3	ENST00000369483.5	TSL:5	c.3123delC	p.Asp1041GlufsTer14	frameshift	Exon 11 of 12	ENSP00000358495.1	O75054-2

Frequencies

GnomAD3 genomes AF: 0.000365 AC: 52 AN: 142398 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000248

Gnomad AMI AF: 0.00831

Gnomad AMR AF: 0.00134

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000414

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000270 AC: 6 AN: 222140 AF XY: 0.0000167

Gnomad AFR exome AF: 0.0000649

Gnomad AMR exome AF: 0.0000310

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000417

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000197 AC: 285 AN: 1449566 Hom.: 0 Cov.: 40 AF XY: 0.000204 AC XY: 147 AN XY: 721438

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000122 AC: 4 AN: 32780

American (AMR) AF: 0.000270 AC: 12 AN: 44470

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25860

East Asian (EAS) AF: 0.00 AC: 0 AN: 38818

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51098

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5740

European-Non Finnish (NFE) AF: 0.000229 AC: 253 AN: 1105074

Other (OTH) AF: 0.000218 AC: 13 AN: 59682

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000365 AC: 52 AN: 142532 Hom.: 0 Cov.: 28 AF XY: 0.000375 AC XY: 26 AN XY: 69354

African (AFR) AF: 0.0000247 AC: 1 AN: 40518

American (AMR) AF: 0.00134 AC: 19 AN: 14216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3302

East Asian (EAS) AF: 0.00 AC: 0 AN: 5048

South Asian (SAS) AF: 0.00 AC: 0 AN: 4360

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.000414 AC: 26 AN: 62832

Other (OTH) AF: 0.00 AC: 0 AN: 1968

Alfa AF: 0.0000439 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.3
Mutation Taster		=29/171	disease causing (fs/PTC)

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: rs766373978; hg19: chr1-117122284;