NM_020070.4:c.566G>A

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.566G>A(p.Arg189His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00715 in 1,613,992 control chromosomes in the GnomAD database, including 464 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 (★★).

Frequency

Genomes: 𝑓 0.032 ( 217 hom., cov: 32)

Exomes 𝑓: 0.0045 ( 247 hom. )

Consequence

IGLL1
NM_020070.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.220

Publications

6 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024659336).

BP6

Variant 22-23573342-C-T is Benign according to our data. Variant chr22-23573342-C-T is described in ClinVar as Benign. ClinVar VariationId is 487215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGLL1	NM_020070.4 link	c.566G>A	p.Arg189His	missense_variant	Exon 3 of 3	ENST00000330377.3	NP_064455.1	P15814-1
IGLL1	NM_001369906.1 link	c.569G>A	p.Arg190His	missense_variant	Exon 3 of 3		NP_001356835.1
IGLL1	NM_152855.3 link	c.*195G>A		3_prime_UTR_variant	Exon 2 of 2		NP_690594.1	P15814-2
LOC105372957	XR_938078.2 link	n.*244C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGLL1	ENST00000330377.3 link	c.566G>A	p.Arg189His	missense_variant	Exon 3 of 3	1	NM_020070.4	ENSP00000329312.2		P15814-1

Frequencies

GnomAD3 genomes

AF:

0.0323

AC:

4903

AN:

152012

Hom.:

218

Cov.:

show subpopulations

Gnomad AFR

AF:

0.107

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0157

Gnomad ASJ

AF:

0.00836

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.00169

Gnomad OTH

AF:

0.0315

GnomAD2 exomes

AF:

0.00983

AC:

2472

AN:

251436

AF XY:

0.00786

show subpopulations

Gnomad AFR exome

AF:

0.106

Gnomad AMR exome

AF:

0.00934

Gnomad ASJ exome

AF:

0.00953

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00184

Gnomad OTH exome

AF:

0.00961

GnomAD4 exome

AF:

0.00453

AC:

6617

AN:

1461862

Hom.:

247

Cov.:

AF XY:

0.00417

AC XY:

3031

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.112

AC:

3746

AN:

33470

American (AMR)

AF:

0.00999

AC:

447

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00872

AC:

228

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00202

AC:

174

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.0366

AC:

211

AN:

5768

European-Non Finnish (NFE)

AF:

0.00106

AC:

1184

AN:

1112000

Other (OTH)

AF:

0.0103

AC:

625

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

411

821

1232

1642

2053

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

142

284

426

568

710

<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:

0.0323

AC:

4917

AN:

152130

Hom.:

217

Cov.:

AF XY:

0.0320

AC XY:

2379

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.107

AC:

4440

AN:

41458

American (AMR)

AF:

0.0156

AC:

239

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00836

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5138

South Asian (SAS)

AF:

0.00291

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00169

AC:

115

AN:

68008

Other (OTH)

AF:

0.0312

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

212

424

637

849

1061

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<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:

0.0168

Hom.:

Bravo

AF:

0.0369

ESP6500AA

AF:

0.106

AC:

466

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.0116

AC:

1410

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.00251

EpiControl

AF:

0.00290

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Agammaglobulinemia 2, autosomal recessive

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.81

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.068

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.00048

LIST_S2

Benign

0.11

MetaRNN

Benign

0.0025

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.65

PhyloP100

0.22

PrimateAI

Benign

0.42

PROVEAN

Benign

3.6

REVEL

Benign

0.0090

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.024

MPC

0.062

ClinPred

0.0026

GERP RS

-4.3

Varity_R

0.085

gMVP

0.29

Mutation Taster

=98/2

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