1-116579681-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001007237.3(IGSF3):c.3045G>C(p.Glu1015Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IGSF3 NM_001007237.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.334

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, IGSF3
• BP4: Computational evidence support a benign effect (MetaRNN=0.07886112).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGSF3	NM_001007237.3	c.3045G>C	p.Glu1015Asp	missense_variant	10/11	ENST00000369486.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGSF3	ENST00000369486.8	c.3045G>C	p.Glu1015Asp	missense_variant	10/11	1	NM_001007237.3	P4
IGSF3	ENST00000318837.6	c.3105G>C	p.Glu1035Asp	missense_variant	10/11	2		A1
IGSF3	ENST00000369483.5	c.3105G>C	p.Glu1035Asp	missense_variant	11/12	5		A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461556 Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1 AN XY: 727068

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 02, 2024

The c.3105G>C (p.E1035D) alteration is located in exon 11 (coding exon 10) of the IGSF3 gene. This alteration results from a G to C substitution at nucleotide position 3105, causing the glutamic acid (E) at amino acid position 1035 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	5.9
Dann	Benign	0.92
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.46	T;T;.
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.079	T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.71	N;N;N
REVEL	Benign	0.026
Sift	Benign	0.20	T;T;T
Sift4G	Uncertain	0.045	D;D;D
Polyphen		0.65	.;P;.
Vest4		0.20
MutPred		0.27		.;Loss of helix (P = 0.5774);.;
MVP		0.35
MPC		0.50
ClinPred		0.095	T
GERP RS		2.5
Varity_R		0.055
gMVP		0.40

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: rs1233679735; hg19: chr1-117122303;