chr1-116579442-C-T

Variant names:

• chr1-116579442-C-T
• rs144889330
• NM_001007237.3:c.3284G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001007237.3(IGSF3):​c.3284G>A​(p.Arg1095Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000802 in 1,608,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000081 (0 hom.)
• Consequence: IGSF3 NM_001007237.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.106313854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGSF3	NM_001007237.3	c.3284G>A	p.Arg1095Gln	missense_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.3284G>A	p.Arg1095Gln	missense_variant	Exon 10 of 11	1	NM_001007237.3	ENSP00000358498.4
IGSF3	ENST00000318837.6	c.3344G>A	p.Arg1115Gln	missense_variant	Exon 10 of 11	2		ENSP00000321184.6
IGSF3	ENST00000369483.5	c.3344G>A	p.Arg1115Gln	missense_variant	Exon 11 of 12	5		ENSP00000358495.1

Frequencies

GnomAD3 genomes AF: 0.0000724 AC: 11 AN: 151920 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000138 AC: 34 AN: 247118 Hom.: 0 AF XY: 0.000135 AC XY: 18 AN XY: 133734

Gnomad AFR exome AF: 0.0000624

Gnomad AMR exome AF: 0.000409

Gnomad ASJ exome AF: 0.000728

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000133

Gnomad FIN exome AF: 0.0000933

Gnomad NFE exome AF: 0.0000449

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000810 AC: 118 AN: 1456776 Hom.: 0 Cov.: 31 AF XY: 0.0000870 AC XY: 63 AN XY: 724180

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.000361

Gnomad4 ASJ exome AF: 0.000467

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000140

Gnomad4 FIN exome AF: 0.0000377

Gnomad4 NFE exome AF: 0.0000613

Gnomad4 OTH exome AF: 0.0000997

GnomAD4 genome AF: 0.0000724 AC: 11 AN: 151920 Hom.: 0 Cov.: 32 AF XY: 0.0000809 AC XY: 6 AN XY: 74198

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000101 Hom.: 0

Bravo AF: 0.0000831

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000989 AC: 12

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3344G>A (p.R1115Q) alteration is located in exon 11 (coding exon 10) of the IGSF3 gene. This alteration results from a G to A substitution at nucleotide position 3344, causing the arginine (R) at amino acid position 1115 to be replaced by a glutamine (Q). 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	0.094
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	.;T;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.79	T;T;.
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.8	.;L;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.71	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.063	T;T;T
Sift4G	Benign	0.21	T;T;T
Polyphen		0.91	.;P;.
Vest4		0.24
MVP		0.36
MPC		0.65
ClinPred		0.042	T
GERP RS		4.6
Varity_R		0.13
gMVP		0.53

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: rs144889330; hg19: chr1-117122064;