22-23575005-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020070.4(IGLL1):c.284C>A(p.Thr95Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,610,198 control chromosomes in the GnomAD database, including 306 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T95M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.025 ( 98 hom., cov: 32)

Exomes 𝑓: 0.012 ( 208 hom. )

Consequence

IGLL1
NM_020070.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.204

Publications

14 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027917027).

BP6

Variant 22-23575005-G-T is Benign according to our data. Variant chr22-23575005-G-T is described in ClinVar as Benign. ClinVar VariationId is 471476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
IGLL1	NM_020070.4 link	c.284C>A	p.Thr95Lys	missense_variant	Exon 2 of 3	ENST00000330377.3	NP_064455.1
IGLL1	NM_001369906.1 link	c.287C>A	p.Thr96Lys	missense_variant	Exon 2 of 3		NP_001356835.1
IGLL1	NM_152855.3 link	c.207-1420C>A		intron_variant	Intron 1 of 1		NP_690594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
IGLL1	ENST00000330377.3 link	c.284C>A	p.Thr95Lys	missense_variant	Exon 2 of 3	1	NM_020070.4	ENSP00000329312.2
IGLL1	ENST00000249053.3 link	c.207-1420C>A		intron_variant	Intron 1 of 1	1		ENSP00000249053.3
IGLL1	ENST00000438703.1 link	c.287C>A	p.Thr96Lys	missense_variant	Exon 2 of 3	2		ENSP00000403391.1

Frequencies

GnomAD3 genomes

AF:

0.0249

AC:

3781

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0589

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0210

Gnomad ASJ

AF:

0.00835

Gnomad EAS

AF:

0.0125

Gnomad SAS

AF:

0.0141

Gnomad FIN

AF:

0.00169

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0113

Gnomad OTH

AF:

0.0239

GnomAD2 exomes

AF:

0.0149

AC:

3748

AN:

251362

AF XY:

0.0140

show subpopulations

Gnomad AFR exome

AF:

0.0579

Gnomad AMR exome

AF:

0.0181

Gnomad ASJ exome

AF:

0.0116

Gnomad EAS exome

AF:

0.0109

Gnomad FIN exome

AF:

0.00152

Gnomad NFE exome

AF:

0.0113

Gnomad OTH exome

AF:

0.0181

GnomAD4 exome

AF:

0.0124

AC:

18127

AN:

1457950

Hom.:

208

Cov.:

AF XY:

0.0122

AC XY:

8854

AN XY:

725510

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0585

AC:

1941

AN:

33166

American (AMR)

AF:

0.0189

AC:

845

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

271

AN:

26118

East Asian (EAS)

AF:

0.0147

AC:

585

AN:

39682

South Asian (SAS)

AF:

0.0129

AC:

1114

AN:

86190

European-Finnish (FIN)

AF:

0.00161

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00851

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0111

AC:

12309

AN:

1108662

Other (OTH)

AF:

0.0154

AC:

927

AN:

60248

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.372

Heterozygous variant carriers

665

1331

1996

2662

3327

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

516

1032

1548

2064

2580

<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:

0.0249

AC:

3792

AN:

152248

Hom.:

Cov.:

AF XY:

0.0232

AC XY:

1728

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0588

AC:

2440

AN:

41524

American (AMR)

AF:

0.0210

AC:

321

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00835

AC:

AN:

3472

East Asian (EAS)

AF:

0.0126

AC:

AN:

5176

South Asian (SAS)

AF:

0.0141

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00169

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0113

AC:

770

AN:

68004

Other (OTH)

AF:

0.0274

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

180

360

539

719

899

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.243

Hom.:

6615

Bravo

AF:

0.0288

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.0143

AC:

ESP6500AA

AF:

0.0452

AC:

199

ESP6500EA

AF:

0.00791

AC:

ExAC

AF:

0.0164

AC:

1995

EpiCase

AF:

0.0104

EpiControl

AF:

0.00990

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 13, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25363768) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Agammaglobulinemia 2, autosomal recessive

Benign:2

Nov 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.57

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.18

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0065

LIST_S2

Benign

0.063

T;T

MetaRNN

Benign

0.0028

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.0

N;.

PhyloP100

0.20

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.020

N;N

REVEL

Benign

0.12

Sift

Benign

0.19

T;T

Sift4G

Benign

0.33

T;.

Polyphen

0.019

B;.

Vest4

0.068

MPC

0.060

ClinPred

0.0014

GERP RS

0.47

Varity_R

0.14

gMVP

0.25

Mutation Taster

=100/0

polymorphism (auto)

(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