rs532338576

Variant names:

• chr22-23575030-AC-A
• rs532338576
• NM_020070.4:c.258delG

Your query was ambiguous. Multiple possible variants found:

• chr22-23575030-AC-A
• chr22-23575030-AC-ACC

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP5 BS2

The NM_020070.4(IGLL1):​c.258delG​(p.Gln88AsnfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,613,356 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (3 hom.)
• Consequence: IGLL1 NM_020070.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 O:1
• Conservation: PhyloP100: 0.191

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP5: Variant 22-23575030-AC-A is Pathogenic according to our data. Variant chr22-23575030-AC-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 236015.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2, not_provided=1}. Variant chr22-23575030-AC-A is described in Lovd as [Likely_pathogenic].
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGLL1	NM_020070.4	c.258delG	p.Gln88AsnfsTer7	frameshift_variant	Exon 2 of 3	ENST00000330377.3	NP_064455.1
IGLL1	NM_001369906.1	c.261delG	p.Gln89AsnfsTer7	frameshift_variant	Exon 2 of 3		NP_001356835.1
IGLL1	NM_152855.3	c.207-1446delG		intron_variant	Intron 1 of 1		NP_690594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGLL1	ENST00000330377.3	c.258delG	p.Gln88AsnfsTer7	frameshift_variant	Exon 2 of 3	1	NM_020070.4	ENSP00000329312.2
IGLL1	ENST00000249053.3	c.207-1446delG		intron_variant	Intron 1 of 1	1		ENSP00000249053.3
IGLL1	ENST00000438703.1	c.261delG	p.Gln89AsnfsTer7	frameshift_variant	Exon 2 of 3	2		ENSP00000403391.1

Frequencies

GnomAD3 genomes AF: 0.000991 AC: 150 AN: 151380 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000389

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00132

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000418

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00152

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000966 AC: 243 AN: 251458 Hom.: 1 AF XY: 0.000949 AC XY: 129 AN XY: 135908

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00175

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.00134 AC: 1960 AN: 1461858 Hom.: 3 Cov.: 31 AF XY: 0.00122 AC XY: 886 AN XY: 727230

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00165

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00159

Gnomad4 OTH exome AF: 0.00149

GnomAD4 genome AF: 0.000990 AC: 150 AN: 151498 Hom.: 0 Cov.: 32 AF XY: 0.000946 AC XY: 70 AN XY: 74028

Gnomad4 AFR AF: 0.000388

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000418

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00152

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.00117 Hom.: 0

Bravo AF: 0.000971

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Agammaglobulinemia 2, autosomal recessive Pathogenic:3 Uncertain:1 Other:1

Nov 09, 2022

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in the literature in 4 individuals with features of a primary immunodeficency in the homozygous state (Mones 2014 PMID:25502423 {alt nomenclature-c.258delG,p.Gly86fs} Platt 2021 PMID:32888943, Sogkas 2021 PMID:34619682). This variant is present in the Genome Aggregation Database (Highest reported MAF 0.1% [103/67812]; https://gnomad.broadinstitute.org/variant/22-23575030-AC-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID: 236015). Evolutionary conservation and computational prediction tools for this variant are limited or unavailable. This variant is a deletion of 1 nucleotide and creates a premature stop codon 7 amino acid positions downstream from this location, which is expected to result in an absent or abnormal protein. Loss of function variants have been reported in association with disease for this gene however, evidence is still limited at this time. In summary, this variant is classified as pathogenic based on the data above. -

-

GenomeConnect - Brain Gene Registry

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 06-14-2021 by Lab The Children's Hospital of Philadelphia. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln88Asnfs*7) in the IGLL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 126 amino acid(s) of the IGLL1 protein. This variant is present in population databases (rs532338576, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with Agammaglobulinemia, primary immunodeficiency, and/or reduced B lymphocytes and increased susceptibility to bacterial infection (PMID: 25502423, 32888943, 34619682). This variant is also known as c.[258_258del]. ClinVar contains an entry for this variant (Variation ID: 236015). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Jun 13, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.092%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with IGLL1 related disorder (ClinVar ID: VCV000236015 / PMID: 32888943). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

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: rs532338576; hg19: chr22-23917217;