22-23573314-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020070.4(IGLL1):c.594C>A(p.His198Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000189 in 1,613,110 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 (★★). Synonymous variant affecting the same amino acid position (i.e. H198H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: IGLL1 NM_020070.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.122

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGLL1	NM_020070.4	c.594C>A	p.His198Gln	missense_variant	3/3	ENST00000330377.3
IGLL1	NM_001369906.1	c.597C>A	p.His199Gln	missense_variant	3/3
IGLL1	NM_152855.3	c.*223C>A		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGLL1	ENST00000330377.3	c.594C>A	p.His198Gln	missense_variant	3/3	1	NM_020070.4	P1
IGLL1	ENST00000249053.3	c.*223C>A		3_prime_UTR_variant	2/2	1
	ENST00000458318.2	n.391-151G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 151446 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000777

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000203 AC: 51 AN: 251250 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135820

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000192 AC: 281 AN: 1461544 Hom.: 0 Cov.: 32 AF XY: 0.000191 AC XY: 139 AN XY: 727062

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000730

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000187

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000158 AC: 24 AN: 151566 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74116

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000779

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0234 Hom.: 330

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Agammaglobulinemia 2, autosomal recessive Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jul 09, 2020	The homozygous p.His198Gln missense variant identified in IGLL1 has not been reported in affected individuals in the literature. The variant has 0.0001262 allele frequency in the genomAD(v3) database (18 out of 142,618 heterozygous alleles, no homozygote) indicating it is a rare allele in the populations represented in this database. The variant affects an evolutionary conserved Histidine residue at position 198 and is predicted deleterious by multiple in silico prediction tools. Based on the current evidence, the p.His198Gln variant in the IGLL1gene is assessed as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 198 of the IGLL1 protein (p.His198Gln). 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 variant has not been reported in the literature in individuals affected with IGLL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1021143). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	9.9
Dann	Benign	0.87
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0096	T
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	0.73	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.64		Loss of sheet (P = 0.0817);
MVP		0.16
MPC		0.35
ClinPred		0.33	T
GERP RS		-4.2
Varity_R		0.88
gMVP		0.76

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: rs1064418; hg19: chr22-23915501;