rs140494226

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The ENST00000249053.3(IGLL1):c.220C>T(p.His74Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,613,226 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H74Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 1 hom. )

Consequence

IGLL1
ENST00000249053.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.23

Publications

2 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:

ENSG00000224277 (HGNC:):

ENSG00000224277 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009215236).

BP6

Variant 22-23573572-G-A is Benign according to our data. Variant chr22-23573572-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 538833.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 2 Unknown,AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
IGLL1	NM_020070.4 link	c.336C>T	p.Ala112Ala	synonymous_variant	Exon 3 of 3	ENST00000330377.3	NP_064455.1
IGLL1	NM_152855.3 link	c.220C>T	p.His74Tyr	missense_variant	Exon 2 of 2		NP_690594.1
IGLL1	NM_001369906.1 link	c.339C>T	p.Ala113Ala	synonymous_variant	Exon 3 of 3		NP_001356835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
IGLL1	ENST00000249053.3 link	c.220C>T	p.His74Tyr	missense_variant	Exon 2 of 2	1		ENSP00000249053.3
IGLL1	ENST00000330377.3 link	c.336C>T	p.Ala112Ala	synonymous_variant	Exon 3 of 3	1	NM_020070.4	ENSP00000329312.2
IGLL1	ENST00000438703.1 link	c.339C>T	p.Ala113Ala	synonymous_variant	Exon 3 of 3	2		ENSP00000403391.1
ENSG00000224277	ENST00000458318.2 link	n.*65G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00113

AC:

172

AN:

151900

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000558

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00270

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00156

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000805

AC:

202

AN:

251056

AF XY:

0.000766

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00136

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.000944

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00136

AC:

1990

AN:

1461208

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

962

AN XY:

726918

show subpopulations

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

African (AFR)

AF:

0.000508

AC:

AN:

33454

American (AMR)

AF:

0.000313

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26128

East Asian (EAS)

AF:

0.000756

AC:

AN:

39698

South Asian (SAS)

AF:

0.000383

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000524

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.00151

AC:

1679

AN:

1111486

Other (OTH)

AF:

0.00244

AC:

147

AN:

60352

⚠️ 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: 0.388

Heterozygous variant carriers

141

211

282

352

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<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:

0.00116

AC:

177

AN:

152018

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.000557

AC:

AN:

41324

American (AMR)

AF:

0.00131

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00271

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00156

AC:

106

AN:

68010

Other (OTH)

AF:

0.00284

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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:

0.000865

Hom.:

Bravo

AF:

0.00113

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000873

AC:

106

EpiCase

AF:

0.00213

EpiControl

AF:

0.00130

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Agammaglobulinemia 2, autosomal recessive

Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.51

CADD

Benign

1.3

(source)

DANN

Benign

0.49

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

LIST_S2

Benign

0.26

M_CAP

Benign

0.0026

MetaRNN

Benign

0.0092

MetaSVM

Benign

-1.0

PhyloP100

-1.2

PROVEAN

Benign

0.67

Sift

Benign

0.17

Sift4G

Benign

0.46

Vest4

0.13

ClinPred

0.0026

GERP RS

-4.9

Mutation Taster

=99/1

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