rs145176864

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020070.4(IGLL1):c.464C>T(p.Pro155Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,613,066 control chromosomes in the GnomAD database, including 228 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 62 hom., cov: 32)

Exomes 𝑓: 0.012 ( 166 hom. )

Consequence

IGLL1
NM_020070.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.940

Publications

9 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=0.0038833618).

BP6

Variant 22-23573444-G-A is Benign according to our data. Variant chr22-23573444-G-A is described in ClinVar as Benign. ClinVar VariationId is 439823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0223 (3393/151964) while in subpopulation AFR AF = 0.0498 (2068/41488). AF 95% confidence interval is 0.0481. There are 62 homozygotes in GnomAd4. There are 1669 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 62 Unknown,AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGLL1	NM_020070.4 link	c.464C>T	p.Pro155Leu	missense_variant	Exon 3 of 3	ENST00000330377.3	NP_064455.1	P15814-1
IGLL1	NM_001369906.1 link	c.467C>T	p.Pro156Leu	missense_variant	Exon 3 of 3		NP_001356835.1
IGLL1	NM_152855.3 link	c.*93C>T		3_prime_UTR_variant	Exon 2 of 2		NP_690594.1	P15814-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IGLL1	ENST00000330377.3 link	c.464C>T	p.Pro155Leu	missense_variant	Exon 3 of 3	1	NM_020070.4	ENSP00000329312.2	P15814-1
IGLL1	ENST00000249053.3 link	c.*93C>T		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000249053.3	P15814-2
IGLL1	ENST00000438703.1 link	c.467C>T	p.Pro156Leu	missense_variant	Exon 3 of 3	2		ENSP00000403391.1	C9JEE0
ENSG00000224277	ENST00000458318.2 link	n.391-21G>A		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.0223

AC:

3383

AN:

151846

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0498

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0214

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.00348

Gnomad SAS

AF:

0.0195

Gnomad FIN

AF:

0.00481

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0108

Gnomad OTH

AF:

0.0229

GnomAD2 exomes

AF:

0.0143

AC:

3590

AN:

251226

AF XY:

0.0143

show subpopulations

Gnomad AFR exome

AF:

0.0531

Gnomad AMR exome

AF:

0.0110

Gnomad ASJ exome

AF:

0.0140

Gnomad EAS exome

AF:

0.00375

Gnomad FIN exome

AF:

0.00610

Gnomad NFE exome

AF:

0.0114

Gnomad OTH exome

AF:

0.0158

GnomAD4 exome

AF:

0.0117

AC:

17047

AN:

1461102

Hom.:

166

Cov.:

AF XY:

0.0120

AC XY:

8752

AN XY:

726862

show subpopulations

African (AFR)

AF:

0.0511

AC:

1705

AN:

33386

American (AMR)

AF:

0.0118

AC:

529

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0133

AC:

347

AN:

26130

East Asian (EAS)

AF:

0.00489

AC:

194

AN:

39698

South Asian (SAS)

AF:

0.0204

AC:

1758

AN:

86240

European-Finnish (FIN)

AF:

0.00661

AC:

353

AN:

53408

Middle Eastern (MID)

AF:

0.0201

AC:

116

AN:

5760

European-Non Finnish (NFE)

AF:

0.0101

AC:

11211

AN:

1111436

Other (OTH)

AF:

0.0138

AC:

834

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

955

1910

2866

3821

4776

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

450

900

1350

1800

2250

<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:

0.0223

AC:

3393

AN:

151964

Hom.:

Cov.:

AF XY:

0.0225

AC XY:

1669

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.0498

AC:

2068

AN:

41488

American (AMR)

AF:

0.0214

AC:

327

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0127

AC:

AN:

3468

East Asian (EAS)

AF:

0.00349

AC:

AN:

5164

South Asian (SAS)

AF:

0.0195

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00481

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0108

AC:

735

AN:

67810

Other (OTH)

AF:

0.0227

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

152

305

457

610

762

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0179

Hom.:

Bravo

AF:

0.0248

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.0515

AC:

227

ESP6500EA

AF:

0.0105

AC:

ExAC

AF:

0.0155

AC:

1886

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.0105

EpiControl

AF:

0.0128

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Agammaglobulinemia 2, autosomal recessive

Benign:2

Aug 21, 2024

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 provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.60

CADD

Benign

8.8

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.30

T;.

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.83

T;T

MetaRNN

Benign

0.0039

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.7

L;.

PhyloP100

0.94

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-6.3

D;D

REVEL

Benign

0.074

Sift

Uncertain

0.015

D;D

Sift4G

Uncertain

0.011

D;.

Polyphen

0.084

B;.

Vest4

0.051

MPC

0.064

ClinPred

0.017

GERP RS

1.3

Varity_R

0.29

gMVP

0.27

Mutation Taster

=99/1

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