NM_001007237.3:c.3320G>A

Variant names:

• chr1-116579406-C-T
• rs372235081
• NM_001007237.3:c.3320G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001007237.3(IGSF3):​c.3320G>A​(p.Arg1107His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,572,408 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1107C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (1 hom.)
• Consequence: IGSF3 NM_001007237.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.967

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06146127).
• BP6: Variant 1-116579406-C-T is Benign according to our data. Variant chr1-116579406-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3108903.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGSF3	NM_001007237.3	c.3320G>A	p.Arg1107His	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.3320G>A	p.Arg1107His	missense_variant	Exon 10 of 11	1	NM_001007237.3	ENSP00000358498.4
IGSF3	ENST00000318837.6	c.3380G>A	p.Arg1127His	missense_variant	Exon 10 of 11	2		ENSP00000321184.6
IGSF3	ENST00000369483.5	c.3380G>A	p.Arg1127His	missense_variant	Exon 11 of 12	5		ENSP00000358495.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000320 AC: 7 AN: 218998 Hom.: 0 AF XY: 0.0000509 AC XY: 6 AN XY: 117766

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000562

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000602

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000500 AC: 71 AN: 1420260 Hom.: 1 Cov.: 30 AF XY: 0.0000385 AC XY: 27 AN XY: 701566

Gnomad4 AFR exome AF: 0.0000309

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000509

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000550

Gnomad4 OTH exome AF: 0.0000684

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74332

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000860 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000495 AC: 6

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Sep 20, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	6.2
DANN	Benign	0.57
DEOGEN2	Benign	0.024	.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.66	T;T;.
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.061	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.14	.;N;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.27	N;N;N
REVEL	Benign	0.030
Sift	Benign	0.26	T;T;T
Sift4G	Benign	0.34	T;T;T
Polyphen		0.032	.;B;.
Vest4		0.080
MVP		0.13
MPC		0.69
ClinPred		0.026	T
GERP RS		0.31
Varity_R		0.019
gMVP		0.18

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: rs372235081; hg19: chr1-117122028;