Variant X-131273813-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001555.5(IGSF1):c.3994C>A(p.Leu1332Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,207,495 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000028 ( 0 hom. 9 hem. )

Consequence

IGSF1
NM_001555.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.307

Variant links:

Genes affected

IGSF1 (HGNC:5948): (immunoglobulin superfamily member 1) This gene encodes a member of the immunoglobulin-like domain-containing superfamily. Proteins in this superfamily contain varying numbers of immunoglobulin-like domains and are thought to participate in the regulation of interactions between cells. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2010]

IGSF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.057249308).

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000283 (31/1095839) while in subpopulation NFE AF= 0.0000333 (28/840538). AF 95% confidence interval is 0.0000231. There are 0 homozygotes in gnomad4_exome. There are 9 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAdExome4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGSF1	NM_001555.5 link	c.3994C>A	p.Leu1332Met	missense_variant	20/20	ENST00000361420.8	NP_001546.2	Q8N6C5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGSF1	ENST00000361420.8 link	c.3994C>A	p.Leu1332Met	missense_variant	20/20	1	NM_001555.5	ENSP00000355010.3		Q8N6C5-1

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111656

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33822

show subpopulations

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000377

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000553

AC:

AN:

180918

Hom.:

AF XY:

0.00

AC XY:

AN XY:

65472

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:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000283

AC:

AN:

1095839

Hom.:

Cov.:

AF XY:

0.0000249

AC XY:

AN XY:

361303

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000285

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:

0.0000333

Gnomad4 OTH exome

AF:

0.0000435

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111656

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33822

show subpopulations

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:

0.00

Gnomad4 NFE

AF:

0.0000377

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2024

The c.4009C>A (p.L1337M) alteration is located in exon 20 (coding exon 19) of the IGSF1 gene. This alteration results from a C to A substitution at nucleotide position 4009, causing the leucine (L) at amino acid position 1337 to be replaced by a methionine (M). 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

0.092

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.82

CADD

Benign

6.2

DANN

Benign

0.95

DEOGEN2

Benign

0.036

.;T;.;.

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.51

.;T;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.057

T;T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.69

.;N;.;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.21

N;N;N;N

REVEL

Benign

0.031

Sift

Uncertain

0.014

D;D;D;D

Sift4G

Benign

0.063

T;T;T;T

Polyphen

0.38

B;P;.;B

Vest4

0.17

MutPred

0.26

.;Loss of catalytic residue at L1332 (P = 0.005);.;.;

MVP

0.093

MPC

0.19

ClinPred

0.067

GERP RS

2.2

Varity_R

0.12

gMVP

0.21

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

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