rs1064422

Positions:

• chr22-23573483-G-A

Variant summary

Our verdict is Likely benign. Variant got -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).

• 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3 B:1
• Conservation: PhyloP100: 5.74

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]

ENSG00000224277 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.105534405).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGLL1	NM_020070.4	c.425C>T	p.Pro142Leu	missense_variant	3/3	ENST00000330377.3	NP_064455.1
IGLL1	NM_001369906.1	c.428C>T	p.Pro143Leu	missense_variant	3/3		NP_001356835.1
IGLL1	NM_152855.3	c.*54C>T		3_prime_UTR_variant	2/2		NP_690594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGLL1	ENST00000330377.3	c.425C>T	p.Pro142Leu	missense_variant	3/3	1	NM_020070.4	ENSP00000329312.2
IGLL1	ENST00000249053.3	c.*54C>T		3_prime_UTR_variant	2/2	1		ENSP00000249053.3
IGLL1	ENST00000438703.1	c.428C>T	p.Pro143Leu	missense_variant	3/3	2		ENSP00000403391.1
ENSG00000224277	ENST00000458318.2	n.409G>A		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 154 AN: 151922 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000299 AC: 75 AN: 251082 Hom.: 0 AF XY: 0.000228 AC XY: 31 AN XY: 135692

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 SAS exome AF: 0.0000980

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.: 1 Cov.: 33 AF XY: 0.000855 AC XY: 621 AN XY: 726092

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00299

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000971

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.00101 AC: 154 AN: 152040 Hom.: 0 Cov.: 32 AF XY: 0.000996 AC XY: 74 AN XY: 74316

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00178

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.000527 Hom.: 0

ExAC AF: 0.000214 AC: 26

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Agammaglobulinemia 2, autosomal recessive Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 05, 1998	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	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. -

not provided Pathogenic:1 Benign:1

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 01, 2018	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 patients’ 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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	IGLL1: BP4 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

May 03, 2020

- -

IGLL1-related condition Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 11, 2024

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	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.41	T;.
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Pathogenic	3.6	H;.
PrimateAI	Uncertain	0.49	T
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	T
GERP RS		1.4
Varity_R		0.57
gMVP		0.73

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

Other links and lift over

dbSNP: rs1064422; hg19: chr22-23915670; COSMIC: COSV50770279; COSMIC: COSV50770279;