GeneBe

22-23575005-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020070.4(IGLL1):​c.284C>G​(p.Thr95Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T95K) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

IGLL1
NM_020070.4 missense

Scores

19

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.204

Publications

14 publications found
Variant links:
Genes affected
IGLL1 (HGNC:5870): (immunoglobulin lambda like polypeptide 1) The preB cell receptor is found on the surface of proB and preB cells, where it is involved in transduction of signals for cellular proliferation, differentiation from the proB cell to the preB cell stage, allelic exclusion at the Ig heavy chain gene locus, and promotion of Ig light chain gene rearrangements. The preB cell receptor is composed of a membrane-bound Ig mu heavy chain in association with a heterodimeric surrogate light chain. This gene encodes one of the surrogate light chain subunits and is a member of the immunoglobulin gene superfamily. This gene does not undergo rearrangement. Mutations in this gene can result in B cell deficiency and agammaglobulinemia, an autosomal recessive disease in which few or no gamma globulins or antibodies are made. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
IGLL1 Gene-Disease associations (from GenCC):
  • agammaglobulinemia 2, autosomal recessive
    Inheritance: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
  • autosomal agammaglobulinemia
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.07611817).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IGLL1NM_020070.4 linkc.284C>G p.Thr95Arg missense_variant Exon 2 of 3 ENST00000330377.3 NP_064455.1
IGLL1NM_001369906.1 linkc.287C>G p.Thr96Arg missense_variant Exon 2 of 3 NP_001356835.1
IGLL1NM_152855.3 linkc.207-1420C>G intron_variant Intron 1 of 1 NP_690594.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IGLL1ENST00000330377.3 linkc.284C>G p.Thr95Arg missense_variant Exon 2 of 3 1 NM_020070.4 ENSP00000329312.2
IGLL1ENST00000249053.3 linkc.207-1420C>G intron_variant Intron 1 of 1 1 ENSP00000249053.3
IGLL1ENST00000438703.1 linkc.287C>G p.Thr96Arg missense_variant Exon 2 of 3 2 ENSP00000403391.1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251362
AF XY:
0.00000736
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
6.84e-7
AC:
1
AN:
1461502
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727080
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
33444
American (AMR)
AF:
0.00
AC:
0
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86254
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
9.00e-7
AC:
1
AN:
1111678
Other (OTH)
AF:
0.00
AC:
0
AN:
60382
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.325
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.052
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
0.55
DANN
Benign
0.82
DEOGEN2
Benign
0.19
T;.
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.00050
N
LIST_S2
Benign
0.078
T;T
M_CAP
Benign
0.0045
T
MetaRNN
Benign
0.076
T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
-0.34
N;.
PhyloP100
0.20
PrimateAI
Benign
0.48
T
PROVEAN
Benign
-0.29
N;N
REVEL
Benign
0.14
Sift
Benign
0.26
T;T
Sift4G
Benign
0.38
T;.
Polyphen
0.027
B;.
Vest4
0.12
MutPred
0.35
Gain of MoRF binding (P = 0.0091);.;
MVP
0.12
MPC
0.058
ClinPred
0.079
T
GERP RS
0.47
Varity_R
0.23
gMVP
0.29
Mutation Taster
=100/0
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs116041505; hg19: chr22-23917192; API