22-23579994-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020070.4(IGLL1):c.197G>A(p.Arg66Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000841 in 1,581,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R66W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000087 ( 0 hom. )

Consequence

IGLL1
NM_020070.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.03

Publications

1 publications found

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 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

IGLL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008784562).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
IGLL1	NM_020070.4 link	c.197G>A	p.Arg66Gln	missense_variant	Exon 1 of 3	ENST00000330377.3	NP_064455.1
IGLL1	NM_001369906.1 link	c.197G>A	p.Arg66Gln	missense_variant	Exon 1 of 3		NP_001356835.1
IGLL1	NM_152855.3 link	c.197G>A	p.Arg66Gln	missense_variant	Exon 1 of 2		NP_690594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
IGLL1	ENST00000330377.3 link	c.197G>A	p.Arg66Gln	missense_variant	Exon 1 of 3	1	NM_020070.4	ENSP00000329312.2
IGLL1	ENST00000249053.3 link	c.197G>A	p.Arg66Gln	missense_variant	Exon 1 of 2	1		ENSP00000249053.3
IGLL1	ENST00000438703.1 link	c.197G>A	p.Arg66Gln	missense_variant	Exon 1 of 3	2		ENSP00000403391.1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000210

AC:

AN:

195234

AF XY:

0.000279

show subpopulations

Gnomad AFR exome

AF:

0.000178

Gnomad AMR exome

AF:

0.000132

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00130

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000582

Gnomad OTH exome

AF:

0.000393

GnomAD4 exome

AF:

0.0000868

AC:

124

AN:

1428902

Hom.:

Cov.:

AF XY:

0.0000973

AC XY:

AN XY:

708982

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

33056

American (AMR)

AF:

0.0000969

AC:

AN:

41288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25552

East Asian (EAS)

AF:

0.000881

AC:

AN:

38578

South Asian (SAS)

AF:

0.000242

AC:

AN:

82564

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42438

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.0000491

AC:

AN:

1100368

Other (OTH)

AF:

0.000135

AC:

AN:

59358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41536

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00116

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.000181

ExAC

AF:

0.000117

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Agammaglobulinemia 2, autosomal recessive

Uncertain:1

Aug 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 66 of the IGLL1 protein (p.Arg66Gln). This variant is present in population databases (rs569884568, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 572361). 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 tolerated. 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

Benign

0.11

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.54

CADD

Benign

6.7

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.13

.;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0091

LIST_S2

Benign

0.29

T;T;T

M_CAP

Benign

0.0011

MetaRNN

Benign

0.0088

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.34

N;N;.

PhyloP100

-1.0

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.69

N;N;N

REVEL

Benign

0.24

Sift

Benign

0.41

T;T;T

Sift4G

Benign

0.52

T;T;.

Polyphen

0.79

.;P;.

Vest4

0.078

MutPred

0.28

Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);

MVP

0.11

MPC

0.058

ClinPred

0.0085

GERP RS

-1.6

PromoterAI

0.00050

Neutral

(source)

Varity_R

0.025

gMVP

0.24

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over