rs74315491

Variant names:

• chr22-23580127-G-A
• rs74315491
• NM_020070.4:c.64C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020070.4(IGLL1):​c.64C>T​(p.Gln22*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000355 in 1,410,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: IGLL1 NM_020070.4 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: -0.129
• Publications: 1 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGLL1	NM_020070.4	c.64C>T	p.Gln22*	stop_gained	Exon 1 of 3	ENST00000330377.3	NP_064455.1
IGLL1	NM_001369906.1	c.64C>T	p.Gln22*	stop_gained	Exon 1 of 3		NP_001356835.1
IGLL1	NM_152855.3	c.64C>T	p.Gln22*	stop_gained	Exon 1 of 2		NP_690594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGLL1	ENST00000330377.3	c.64C>T	p.Gln22*	stop_gained	Exon 1 of 3	1	NM_020070.4	ENSP00000329312.2
IGLL1	ENST00000249053.3	c.64C>T	p.Gln22*	stop_gained	Exon 1 of 2	1		ENSP00000249053.3
IGLL1	ENST00000438703.1	c.64C>T	p.Gln22*	stop_gained	Exon 1 of 3	2		ENSP00000403391.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000121 AC: 2 AN: 164664 AF XY: 0.0000112

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000118

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000147

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000355 AC: 5 AN: 1410132 Hom.: 0 Cov.: 31 AF XY: 0.00000430 AC XY: 3 AN XY: 697298

African (AFR) AF: 0.00 AC: 0 AN: 32698

American (AMR) AF: 0.00 AC: 0 AN: 37080

Ashkenazi Jewish (ASJ) AF: 0.0000792 AC: 2 AN: 25244

East Asian (EAS) AF: 0.00 AC: 0 AN: 37576

South Asian (SAS) AF: 0.00 AC: 0 AN: 80380

European-Finnish (FIN) AF: 0.0000223 AC: 1 AN: 44758

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5288

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1088522

Other (OTH) AF: 0.00 AC: 0 AN: 58586

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000172 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Agammaglobulinemia 2, autosomal recessive Pathogenic:1 Uncertain:1

Jan 05, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 15, 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.Gln22*) in the IGLL1 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in IGLL1 cause disease. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with hypogammaglobulinemia (PMID: 9419212). ClinVar contains an entry for this variant (Variation ID: 14824). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Benign	-0.019
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.0044	N
PhyloP100		-0.13
Vest4		0.064
GERP RS		0.60
PromoterAI		-0.046	Neutral
Mutation Taster		=40/160	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs74315491; hg19: chr22-23922314;