Genetic Variant NM_001007237.3:c.3449A>G (chr1-116577448-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001007237.3(IGSF3):c.3449A>G(p.Lys1150Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000178 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 0.000018 ( 0 hom. )

Consequence

IGSF3
NM_001007237.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.36

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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=0.104625314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGSF3	NM_001007237.3 link	c.3449A>G	p.Lys1150Arg	missense_variant	Exon 11 of 11	ENST00000369486.8	NP_001007238.1	O75054-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IGSF3	ENST00000369486.8 link	c.3449A>G	p.Lys1150Arg	missense_variant	Exon 11 of 11	1	NM_001007237.3	ENSP00000358498.4	O75054-1
IGSF3	ENST00000318837.6 link	c.3509A>G	p.Lys1170Arg	missense_variant	Exon 11 of 11	2		ENSP00000321184.6	O75054-2
IGSF3	ENST00000369483.5 link	c.3509A>G	p.Lys1170Arg	missense_variant	Exon 12 of 12	5		ENSP00000358495.1	O75054-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251496

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727248

show subpopulations

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:

0.0000234

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3509A>G (p.K1170R) alteration is located in exon 12 (coding exon 11) of the IGSF3 gene. This alteration results from a A to G substitution at nucleotide position 3509, causing the lysine (K) at amino acid position 1170 to be replaced by an arginine (R). 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

0.075

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.038

.;T;.

Eigen

Benign

-0.12

Eigen_PC

Benign

0.064

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.77

T;T;.

M_CAP

Benign

0.0070

MetaRNN

Benign

0.10

T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

-0.20

.;N;.

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.69

N;N;N

REVEL

Benign

0.18

Sift

Benign

0.24

T;T;T

Sift4G

Benign

0.19

T;T;T

Polyphen

0.35

.;B;.

Vest4

0.15

MutPred

0.44

.;Loss of methylation at K1150 (P = 0.0079);.;

MVP

0.47

MPC

0.48

ClinPred

0.52

GERP RS

4.9

Varity_R

0.086

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over