rs748093509

Variant names:

• chr1-116579656-C-CGTT
• rs748093509
• NM_001007237.3:c.3069_3070insAAC

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3 BP6 BS2

The NM_001007237.3(IGSF3):​c.3069_3070insAAC​(p.Asp1023_Asp1024insAsn) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,581,164 control chromosomes in the GnomAD database, including 12 homozygotes. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (9 hom.)
• Consequence: IGSF3 NM_001007237.3 conservative_inframe_insertion
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.00100
• 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: Likely_benign. The variant received -6 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001007237.3
• BP6: Variant 1-116579656-C-CGTT is Benign according to our data. Variant chr1-116579656-C-CGTT is described in ClinVar as Benign. ClinVar VariationId is 3046067.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAd4 at 3 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.3069_3070insAAC	p.Asp1023_Asp1024insAsn	conservative_inframe_insertion	Exon 10 of 11	NP_001007238.1	O75054-1
	IGSF3	NM_001542.4		c.3129_3130insAAC	p.Asp1043_Asp1044insAsn	conservative_inframe_insertion	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.3069_3070insAAC	p.Asp1023_Asp1024insAsn	conservative_inframe_insertion	Exon 10 of 11	ENSP00000358498.4	O75054-1
	IGSF3	ENST00000318837.6	TSL:2	c.3129_3130insAAC	p.Asp1043_Asp1044insAsn	conservative_inframe_insertion	Exon 10 of 11	ENSP00000321184.6	O75054-2
	IGSF3	ENST00000369483.5	TSL:5	c.3129_3130insAAC	p.Asp1043_Asp1044insAsn	conservative_inframe_insertion	Exon 11 of 12	ENSP00000358495.1	O75054-2

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 296 AN: 137332 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000200

Gnomad AMI AF: 0.00794

Gnomad AMR AF: 0.0000735

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0218

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.000526

GnomAD2 exomes AF: 0.00268 AC: 585 AN: 218442 AF XY: 0.00263

Gnomad AFR exome AF: 0.0000660

Gnomad AMR exome AF: 0.0000625

Gnomad ASJ exome AF: 0.000110

Gnomad EAS exome AF: 0.000168

Gnomad FIN exome AF: 0.0221

Gnomad NFE exome AF: 0.00196

Gnomad OTH exome AF: 0.00260

GnomAD4 exome AF: 0.00136 AC: 1961 AN: 1443696 Hom.: 9 Cov.: 59 AF XY: 0.00133 AC XY: 959 AN XY: 718760

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

African (AFR) AF: 0.0000307 AC: 1 AN: 32580

American (AMR) AF: 0.0000453 AC: 2 AN: 44172

Ashkenazi Jewish (ASJ) AF: 0.000118 AC: 3 AN: 25448

East Asian (EAS) AF: 0.000107 AC: 4 AN: 37252

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85980

European-Finnish (FIN) AF: 0.0185 AC: 952 AN: 51534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5670

European-Non Finnish (NFE) AF: 0.000839 AC: 925 AN: 1101938

Other (OTH) AF: 0.00123 AC: 73 AN: 59122

⚠️ 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: 0.00215 AC: 296 AN: 137468 Hom.: 3 Cov.: 32 AF XY: 0.00263 AC XY: 176 AN XY: 66872

African (AFR) AF: 0.000200 AC: 8 AN: 40058

American (AMR) AF: 0.0000733 AC: 1 AN: 13636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3176

East Asian (EAS) AF: 0.00 AC: 0 AN: 4928

South Asian (SAS) AF: 0.00 AC: 0 AN: 4222

European-Finnish (FIN) AF: 0.0218 AC: 191 AN: 8758

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.00150 AC: 90 AN: 59860

Other (OTH) AF: 0.000520 AC: 1 AN: 1922

Alfa AF: 0.00118 Hom.: 0

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
PhyloP100		-0.0010
Mutation Taster		=81/19	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs748093509; hg19: chr1-117122278;