rs41301291

Positions:

• chr1-116584795-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 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. 14/20 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

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), IGSF3. . Gene score misZ 1.771 (greater than the threshold 3.09). Trascript score misZ 4.0048 (greater than threshold 3.09). GenCC has associacion of gene with familial congenital nasolacrimal duct obstruction.
• 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 id is 402968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-116584795-C-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGSF3	NM_001007237.3	c.2698G>A	p.Val900Met	missense_variant	9/11	ENST00000369486.8	NP_001007238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGSF3	ENST00000369486.8	c.2698G>A	p.Val900Met	missense_variant	9/11	1	NM_001007237.3	ENSP00000358498.4
IGSF3	ENST00000318837.6	c.2758G>A	p.Val920Met	missense_variant	9/11	2		ENSP00000321184.6
IGSF3	ENST00000369483.5	c.2758G>A	p.Val920Met	missense_variant	10/12	5		ENSP00000358495.1

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

GnomAD3 exomes AF: 0.0164 AC: 4114 AN: 251430 Hom.: 55 AF XY: 0.0164 AC XY: 2235 AN XY: 135896

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 SAS exome AF: 0.00470

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

Gnomad4 AFR exome AF: 0.00418

Gnomad4 AMR exome AF: 0.0114

Gnomad4 ASJ exome AF: 0.0555

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00521

Gnomad4 FIN exome AF: 0.0330

Gnomad4 NFE exome AF: 0.0153

Gnomad4 OTH exome AF: 0.0188

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

Gnomad4 AFR AF: 0.00356

Gnomad4 AMR AF: 0.0100

Gnomad4 ASJ AF: 0.0548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00455

Gnomad4 FIN AF: 0.0311

Gnomad4 NFE AF: 0.0172

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.0186 Hom.: 51

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

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;T;.
MetaRNN	Benign	0.0065	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	.;N;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.25	N;N;N
REVEL	Benign	0.21
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.99	D;D;D
Vest4		0.26
MPC		1.1
ClinPred		0.016	T
GERP RS		2.9
Varity_R		0.027
gMVP		0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs41301291; hg19: chr1-117127417;