1-116584795-C-T

Variant names:

• chr1-116584795-C-T
• rs41301291
• NM_001007237.3:c.2698G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001007237.3(IGSF3):​c.2698G>A​(p.Val900Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,614,228 control chromosomes in the GnomAD database, including 267 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (29 hom., cov: 33)
  • Exomes 𝑓: 0.016 (238 hom.)
• Consequence: IGSF3 NM_001007237.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.78
• Publications: 11 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: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0065087676).
• BP6: Variant 1-116584795-C-T is Benign according to our data. Variant chr1-116584795-C-T is described in ClinVar as Benign. ClinVar VariationId is 402968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0137 (2088/152358) while in subpopulation NFE AF = 0.0172 (1169/68036). AF 95% confidence interval is 0.0164. There are 29 homozygotes in GnomAd4. There are 1037 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 AR,Unknown gene

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.2698G>A	p.Val900Met	missense	Exon 9 of 11	NP_001007238.1	O75054-1
	IGSF3	NM_001542.4		c.2758G>A	p.Val920Met	missense	Exon 10 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.2698G>A	p.Val900Met	missense	Exon 9 of 11	ENSP00000358498.4	O75054-1
	IGSF3	ENST00000318837.6	TSL:2	c.2758G>A	p.Val920Met	missense	Exon 9 of 11	ENSP00000321184.6	O75054-2
	IGSF3	ENST00000369483.5	TSL:5	c.2758G>A	p.Val920Met	missense	Exon 10 of 12	ENSP00000358495.1	O75054-2

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2091 AN: 152240 Hom.: 29 Cov.: 33

Gnomad AFR AF: 0.00357

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.0548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00475

Gnomad FIN AF: 0.0311

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0282

GnomAD2 exomes AF: 0.0164 AC: 4114 AN: 251430 AF XY: 0.0164

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.0596

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0328

Gnomad NFE exome AF: 0.0185

Gnomad OTH exome AF: 0.0202

GnomAD4 exome AF: 0.0156 AC: 22748 AN: 1461870 Hom.: 238 Cov.: 31 AF XY: 0.0155 AC XY: 11243 AN XY: 727232

African (AFR) AF: 0.00418 AC: 140 AN: 33480

American (AMR) AF: 0.0114 AC: 509 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0555 AC: 1450 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00521 AC: 449 AN: 86258

European-Finnish (FIN) AF: 0.0330 AC: 1762 AN: 53420

Middle Eastern (MID) AF: 0.0499 AC: 287 AN: 5756

European-Non Finnish (NFE) AF: 0.0153 AC: 17013 AN: 1112004

Other (OTH) AF: 0.0188 AC: 1138 AN: 60392

GnomAD4 genome AF: 0.0137 AC: 2088 AN: 152358 Hom.: 29 Cov.: 33 AF XY: 0.0139 AC XY: 1037 AN XY: 74498

African (AFR) AF: 0.00356 AC: 148 AN: 41586

American (AMR) AF: 0.0100 AC: 153 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0548 AC: 190 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00455 AC: 22 AN: 4834

European-Finnish (FIN) AF: 0.0311 AC: 330 AN: 10620

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0172 AC: 1169 AN: 68036

Other (OTH) AF: 0.0279 AC: 59 AN: 2112

Alfa AF: 0.0165 Hom.: 94

Bravo AF: 0.0126

TwinsUK AF: 0.0162 AC: 60

ALSPAC AF: 0.0140 AC: 54

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0191 AC: 164

ExAC AF: 0.0159 AC: 1935

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0212

EpiControl AF: 0.0186

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.026
Eigen_PC	Benign	-0.048
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.8
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.21
Sift	Benign	0.21	T
Sift4G	Benign	0.17	T
Polyphen		0.99	D
Vest4		0.26
MPC		1.1
ClinPred		0.016	T
GERP RS		2.9
Varity_R		0.027
gMVP		0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41301291; hg19: chr1-117127417;