chr22-23573423-A-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.485T>A(p.Met162Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0272 in 1,613,580 control chromosomes in the GnomAD database, including 771 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. M162T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.039 ( 152 hom., cov: 32)

Exomes 𝑓: 0.026 ( 619 hom. )

Consequence

IGLL1
NM_020070.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.91

Publications

11 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: AR, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), 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=0.0031225085).

BP6

Variant 22-23573423-A-T is Benign according to our data. Variant chr22-23573423-A-T is described in ClinVar as Benign. ClinVar VariationId is 439820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0642 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020070.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IGLL1	NM_020070.4	MANE Select	c.485T>A	p.Met162Lys	missense	Exon 3 of 3	NP_064455.1	P15814-1
IGLL1	NM_001369906.1		c.488T>A	p.Met163Lys	missense	Exon 3 of 3	NP_001356835.1
IGLL1	NM_152855.3		c.*114T>A		3_prime_UTR	Exon 2 of 2	NP_690594.1	P15814-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IGLL1	ENST00000330377.3	TSL:1 MANE Select	c.485T>A	p.Met162Lys	missense	Exon 3 of 3	ENSP00000329312.2	P15814-1
IGLL1	ENST00000249053.3	TSL:1	c.*114T>A		3_prime_UTR	Exon 2 of 2	ENSP00000249053.3	P15814-2
IGLL1	ENST00000438703.1	TSL:2	c.488T>A	p.Met163Lys	missense	Exon 3 of 3	ENSP00000403391.1	C9JEE0

Frequencies

GnomAD3 genomes

AF:

0.0393

AC:

5980

AN:

152058

Hom.:

152

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0663

Gnomad AMI

AF:

0.0669

Gnomad AMR

AF:

0.0241

Gnomad ASJ

AF:

0.0818

Gnomad EAS

AF:

0.0116

Gnomad SAS

AF:

0.0172

Gnomad FIN

AF:

0.0488

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0258

Gnomad OTH

AF:

0.0393

GnomAD2 exomes

AF:

0.0305

AC:

7661

AN:

251276

AF XY:

0.0302

show subpopulations

Gnomad AFR exome

AF:

0.0638

Gnomad AMR exome

AF:

0.0168

Gnomad ASJ exome

AF:

0.0860

Gnomad EAS exome

AF:

0.0118

Gnomad FIN exome

AF:

0.0467

Gnomad NFE exome

AF:

0.0282

Gnomad OTH exome

AF:

0.0351

GnomAD4 exome

AF:

0.0260

AC:

37979

AN:

1461406

Hom.:

619

Cov.:

AF XY:

0.0260

AC XY:

18898

AN XY:

727018

show subpopulations

African (AFR)

AF:

0.0652

AC:

2180

AN:

33452

American (AMR)

AF:

0.0178

AC:

797

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0900

AC:

2352

AN:

26134

East Asian (EAS)

AF:

0.0111

AC:

440

AN:

39694

South Asian (SAS)

AF:

0.0191

AC:

1646

AN:

86240

European-Finnish (FIN)

AF:

0.0451

AC:

2409

AN:

53420

Middle Eastern (MID)

AF:

0.0581

AC:

335

AN:

5762

European-Non Finnish (NFE)

AF:

0.0232

AC:

25811

AN:

1111626

Other (OTH)

AF:

0.0333

AC:

2009

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

2388

4776

7164

9552

11940

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

956

1912

2868

3824

4780

<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:

0.0393

AC:

5985

AN:

152174

Hom.:

152

Cov.:

AF XY:

0.0393

AC XY:

2920

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.0663

AC:

2752

AN:

41524

American (AMR)

AF:

0.0241

AC:

369

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0818

AC:

284

AN:

3470

East Asian (EAS)

AF:

0.0117

AC:

AN:

5144

South Asian (SAS)

AF:

0.0170

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0488

AC:

518

AN:

10620

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0259

AC:

1757

AN:

67966

Other (OTH)

AF:

0.0389

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

274

547

821

1094

1368

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<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:

0.0274

Hom.:

Bravo

AF:

0.0396

TwinsUK

AF:

0.0256

AC:

ALSPAC

AF:

0.0171

AC:

ESP6500AA

AF:

0.0654

AC:

288

ESP6500EA

AF:

0.0293

AC:

252

ExAC

AF:

0.0312

AC:

3789

EpiCase

AF:

0.0277

EpiControl

AF:

0.0345

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Agammaglobulinemia 2, autosomal recessive (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.13

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0031

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.42

PhyloP100

1.9

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.6

REVEL

Benign

0.078

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0050

Polyphen

0.0010

Vest4

0.062

MPC

0.075

ClinPred

0.032

GERP RS

1.4

Varity_R

0.69

gMVP

0.51

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over