chr1-116579662-C-A

Variant names:

• chr1-116579662-C-A
• rs540876761
• NM_001007237.3:c.3064G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001007237.3(IGSF3):​c.3064G>T​(p.Asp1022Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1022N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: IGSF3 NM_001007237.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.429
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.113771915).

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.3064G>T	p.Asp1022Tyr	missense	Exon 10 of 11	NP_001007238.1	O75054-1
	IGSF3	NM_001542.4		c.3124G>T	p.Asp1042Tyr	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.3064G>T	p.Asp1022Tyr	missense	Exon 10 of 11	ENSP00000358498.4	O75054-1
	IGSF3	ENST00000318837.6	TSL:2	c.3124G>T	p.Asp1042Tyr	missense	Exon 10 of 11	ENSP00000321184.6	O75054-2
	IGSF3	ENST00000369483.5	TSL:5	c.3124G>T	p.Asp1042Tyr	missense	Exon 11 of 12	ENSP00000358495.1	O75054-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449692 Hom.: 0 Cov.: 59 AF XY: 0.00 AC XY: 0 AN XY: 721496

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

African (AFR) AF: 0.00 AC: 0 AN: 32782

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 86044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105192

Other (OTH) AF: 0.00 AC: 0 AN: 59686

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.76
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.43
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.017
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.011	D
Polyphen		0.60	P
Vest4		0.30
MutPred		0.31		Gain of phosphorylation at D1022 (P = 3e-04)
MVP		0.10
MPC		0.69
ClinPred		0.37	T
GERP RS		1.7
Varity_R		0.080
gMVP		0.41
Mutation Taster		=92/8	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: rs540876761; hg19: chr1-117122284;