22-23573314-G-T

Position:

chr22-23573314-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_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 (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

IGLL1
NM_020070.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -0.122

Variant links:

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein
IGLL1	NM_020070.4 linkuse as main transcript	c.594C>A	p.His198Gln	missense_variant	3/3	ENST00000330377.3	NP_064455.1
IGLL1	NM_001369906.1 linkuse as main transcript	c.597C>A	p.His199Gln	missense_variant	3/3		NP_001356835.1
IGLL1	NM_152855.3 linkuse as main transcript	c.*223C>A		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 linkuse as main transcript	c.594C>A	p.His198Gln	missense_variant	3/3	1	NM_020070.4	ENSP00000329312	P1	P15814-1
IGLL1	ENST00000249053.3 linkuse as main transcript	c.*223C>A		3_prime_UTR_variant	2/2	1		ENSP00000249053		P15814-2
	ENST00000458318.2 linkuse as main transcript	n.391-151G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

151446

Hom.:

Cov.:

show subpopulations

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:

AN:

251250

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

135820

show subpopulations

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.:

Cov.:

AF XY:

0.000191

AC XY:

139

AN XY:

727062

show subpopulations

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:

AN:

151566

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74116

show subpopulations

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:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	Labcorp Genetics (formerly Invitae), Labcorp	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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.37

CADD

Benign

9.9

DANN

Benign

0.87

DEOGEN2

Benign

0.38

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.69

M_CAP

Benign

0.0096

MetaRNN

Pathogenic

0.86

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.6

MutationTaster

Benign

0.73

D;D

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-7.0

REVEL

Benign

0.27

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.69

MutPred

0.64

Loss of sheet (P = 0.0817);

MVP

0.16

MPC

0.35

ClinPred

0.33

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over