rs74315491

chr22-23580127-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_020070.4(IGLL1):c.64C>T(p.Gln22Ter) 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: IGLL1 NM_020070.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.129

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_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.9 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-23580127-G-A is Pathogenic according to our data. Variant chr22-23580127-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14824.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGLL1	NM_020070.4	c.64C>T	p.Gln22Ter	stop_gained	1/3	ENST00000330377.3
IGLL1	NM_001369906.1	c.64C>T	p.Gln22Ter	stop_gained	1/3
IGLL1	NM_152855.3	c.64C>T	p.Gln22Ter	stop_gained	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGLL1	ENST00000330377.3	c.64C>T	p.Gln22Ter	stop_gained	1/3	1	NM_020070.4	P1
IGLL1	ENST00000249053.3	c.64C>T	p.Gln22Ter	stop_gained	1/2	1
IGLL1	ENST00000438703.1	c.64C>T	p.Gln22Ter	stop_gained	1/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000121 AC: 2 AN: 164664 Hom.: 0 AF XY: 0.0000112 AC XY: 1 AN XY: 89238

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000792

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000223

Gnomad4 NFE exome AF: 0.00000184

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000172 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Agammaglobulinemia 2, autosomal recessive Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 05, 1998

- -

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
MutationTaster	Benign	1.0	A;A
Vest4		0.064
GERP RS		0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs74315491; hg19: chr22-23922314;