chr1-116579662-CG-C

Position:

• chr1-116579662-CG-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001007237.3(IGSF3):​c.3063delC​(p.Asp1021fs) 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 (★).

• 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

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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.146 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• 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 id is 1678181.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGSF3	NM_001007237.3	c.3063delC	p.Asp1021fs	frameshift_variant	10/11	ENST00000369486.8	NP_001007238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGSF3	ENST00000369486.8	c.3063delC	p.Asp1021fs	frameshift_variant	10/11	1	NM_001007237.3	ENSP00000358498.4
IGSF3	ENST00000318837.6	c.3123delC	p.Asp1041fs	frameshift_variant	10/11	2		ENSP00000321184.6
IGSF3	ENST00000369483.5	c.3123delC	p.Asp1041fs	frameshift_variant	11/12	5		ENSP00000358495.1

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

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

Gnomad4 AFR exome AF: 0.000122

Gnomad4 AMR exome AF: 0.000270

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000229

Gnomad4 OTH exome AF: 0.000218

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

Gnomad4 AFR AF: 0.0000247

Gnomad4 AMR AF: 0.00134

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000414

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000439 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

AiLife Diagnostics, AiLife Diagnostics

Feb 26, 2020

- -

Computational scores

Source: dbNSFP v4.3

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: rs766373978; hg19: chr1-117122284;