rs1064422

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_020070.4(IGLL1):c.425C>T(p.Pro142Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00101 in 152,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P142P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00087 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

IGLL1
NM_020070.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:4B:1

Conservation

PhyloP100: 5.74

Publications

10 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

IGLL1 links:

ENSG00000224277 (HGNC:):

ENSG00000224277 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.105534405).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGLL1	NM_020070.4 link	c.425C>T	p.Pro142Leu	missense_variant	Exon 3 of 3	ENST00000330377.3	NP_064455.1	P15814-1
IGLL1	NM_001369906.1 link	c.428C>T	p.Pro143Leu	missense_variant	Exon 3 of 3		NP_001356835.1
IGLL1	NM_152855.3 link	c.*54C>T		3_prime_UTR_variant	Exon 2 of 2		NP_690594.1	P15814-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IGLL1	ENST00000330377.3 link	c.425C>T	p.Pro142Leu	missense_variant	Exon 3 of 3	1	NM_020070.4	ENSP00000329312.2	P15814-1
IGLL1	ENST00000249053.3 link	c.*54C>T		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000249053.3	P15814-2
IGLL1	ENST00000438703.1 link	c.428C>T	p.Pro143Leu	missense_variant	Exon 3 of 3	2		ENSP00000403391.1	C9JEE0
ENSG00000224277	ENST00000458318.2 link	n.409G>A		non_coding_transcript_exon_variant	Exon 4 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.00101

AC:

154

AN:

151922

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00178

Gnomad OTH

AF:

0.000960

GnomAD2 exomes

AF:

0.000299

AC:

AN:

251082

AF XY:

0.000228

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000467

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000866

AC:

1264

AN:

1459548

Hom.:

Cov.:

AF XY:

0.000855

AC XY:

621

AN XY:

726092

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000239

AC:

AN:

33450

American (AMR)

AF:

0.000246

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00299

AC:

AN:

26106

East Asian (EAS)

AF:

0.000101

AC:

AN:

39694

South Asian (SAS)

AF:

0.000162

AC:

AN:

86176

European-Finnish (FIN)

AF:

0.0000936

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000971

AC:

1078

AN:

1109954

Other (OTH)

AF:

0.00109

AC:

AN:

60308

⚠️ 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: 0.350

Heterozygous variant carriers

129

193

258

322

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00101

AC:

154

AN:

152040

Hom.:

Cov.:

AF XY:

0.000996

AC XY:

AN XY:

74316

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000241

AC:

AN:

41454

American (AMR)

AF:

0.000197

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3470

East Asian (EAS)

AF:

0.000581

AC:

AN:

5166

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00178

AC:

121

AN:

67960

Other (OTH)

AF:

0.000950

AC:

AN:

2106

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.399

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000450

Hom.:

ExAC

AF:

0.000214

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Agammaglobulinemia 2, autosomal recessive

Pathogenic:2Uncertain:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 142 of the IGLL1 protein (p.Pro142Leu). This variant is present in population databases (rs1064422, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with B-cell deficiency and hypogammaglobulinemia (PMID: 9419212). ClinVar contains an entry for this variant (Variation ID: 14825). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Dec 02, 2023

Laboratory of Hereditary Immune Disorders, Research Centre for Medical Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant NM_020070.4(IGLL1):c.425C>T, p.(Pro142Leu) was identified in a homozygous state in a female proband diagnosed with agammaglobulinemia, type 2, in Russian pilot NBS project covering more than 200,000 newborns. This variant has been previously reported in the literature (PMID: 9419212) and is listed in gnomAD v2.1.1 117 times, never in homozygous state. The affected amino acid position is evolutionarily conserved, and multiple in silico prediction tools support a deleterious effect. Taken together, the variant meets the following ACMG/AMP criteria and can be classified as likely pathogenic with PM2, PS1, PP4, PP5 criteria. -

Jan 05, 1998

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 24, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Pathogenic:1Benign:1

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

IGLL1: BP4 -

Apr 01, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The IGLL1 c.425C>T; p.Pro142Leu variant (rs1064422, ClinVar variant ID 14825) has been found in two patients with agammaglobulinemia and severely reduced B cell levels; one patient was a compound heterozygote, with a premature stop codon on the other chromosome (Minegishi 1998), and the other was a homozygote (Gemayel 2016). Both patientsâ€™ IGLL1 genes contained several variants that match the sequence of the highly homologous pseudogene IGLL3P, suggesting the possibility of gene conversion events. Functional studies found that the mutant protein appeared to fold incorrectly and it was not secreted by transfected cells (Minegishi 1998). This variant is listed in the genome Aggregation Database (gnomAD) with a non-Finnish European population frequency of 0.07% (identified on 85 out of 126,310 chromosomes). The proline at position 142 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Pro142Leu variant on protein structure and function predict a deleterious effect (SIFT: damaging, PolyPhen-2: probably damaging). Based on the available information, the p.Pro142Leu variant is likely to be pathogenic. -

not specified

Uncertain:1

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

IGLL1-related condition

Uncertain:1

Sep 11, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The IGLL1 c.425C>T variant is predicted to result in the amino acid substitution p.Pro142Leu. This variant was reported in two individuals with primary immunodeficiency, one of which was homozygous, and the other of which had a nonsense variant in trans (Giżewska et al. 2020. PubMed ID: 33178177; Minegishi et al. 1998. PubMed ID: 9419212). This variant is reported in 0.071% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Of note, this variant has been reported in cis along with c.393T>C and c.420T>C, which correspond to reference sequence in the pseudogene and indicates a potential conversion event at this locus (Minegishi et al. 1998. PubMed ID: 9419212). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.41

T;.

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Pathogenic

3.6

H;.

PhyloP100

5.7

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-8.2

D;D

REVEL

Benign

0.23

Sift

Uncertain

0.014

D;D

Sift4G

Benign

0.062

T;.

Polyphen

1.0

D;.

Vest4

0.49

MVP

0.43

MPC

0.35

ClinPred

0.44

GERP RS

1.4

Varity_R

0.57

gMVP

0.73

Mutation Taster

=62/38

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over