rs724160030

Variant names:

• chr1-116579790-CG-C
• rs724160030
• NM_001007237.3:c.2935delC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001007237.3(IGSF3):​c.2935delC​(p.Arg979AlafsTer15) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGSF3 NM_001007237.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.28
• 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: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-116579790-CG-C is Pathogenic according to our data. Variant chr1-116579790-CG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 162496.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGSF3	NM_001007237.3	c.2935delC	p.Arg979AlafsTer15	frameshift_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.2935delC	p.Arg979AlafsTer15	frameshift_variant	Exon 10 of 11	1	NM_001007237.3	ENSP00000358498.4
IGSF3	ENST00000318837.6	c.2995delC	p.Arg999AlafsTer15	frameshift_variant	Exon 10 of 11	2		ENSP00000321184.6
IGSF3	ENST00000369483.5	c.2995delC	p.Arg999AlafsTer15	frameshift_variant	Exon 11 of 12	5		ENSP00000358495.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Familial congenital nasolacrimal duct obstruction Pathogenic:1

Dec 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.3
Mutation Taster		=2/198	disease causing (ClinVar)

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: rs724160030; hg19: chr1-117122412;