NM_020070.4:c.521C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_020070.4(IGLL1):c.521C>T(p.Ala174Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,561,168 control chromosomes in the GnomAD database, including 9 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A174S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0053 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 6 hom. )

Consequence

IGLL1
NM_020070.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.140

Publications

15 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039779544).

BP6

Variant 22-23573387-G-A is Benign according to our data. Variant chr22-23573387-G-A is described in ClinVar as Benign. ClinVar VariationId is 580208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 3 Unknown,AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
IGLL1	NM_020070.4 link	c.521C>T	p.Ala174Val	missense_variant	Exon 3 of 3	ENST00000330377.3	NP_064455.1
IGLL1	NM_001369906.1 link	c.524C>T	p.Ala175Val	missense_variant	Exon 3 of 3		NP_001356835.1
IGLL1	NM_152855.3 link	c.*150C>T		3_prime_UTR_variant	Exon 2 of 2		NP_690594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
IGLL1	ENST00000330377.3 link	c.521C>T	p.Ala174Val	missense_variant	Exon 3 of 3	1	NM_020070.4	ENSP00000329312.2
IGLL1	ENST00000249053.3 link	c.*150C>T		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000249053.3
IGLL1	ENST00000438703.1 link	c.524C>T	p.Ala175Val	missense_variant	Exon 3 of 3	2		ENSP00000403391.1
ENSG00000224277	ENST00000458318.2 link	n.391-78G>A		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.00531

AC:

788

AN:

148494

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0136

Gnomad AMI

AF:

0.00331

Gnomad AMR

AF:

0.00380

Gnomad ASJ

AF:

0.00203

Gnomad EAS

AF:

0.00300

Gnomad SAS

AF:

0.00716

Gnomad FIN

AF:

0.00193

Gnomad MID

AF:

0.00968

Gnomad NFE

AF:

0.00156

Gnomad OTH

AF:

0.00344

GnomAD2 exomes

AF:

0.00501

AC:

1198

AN:

239166

AF XY:

0.00446

show subpopulations

Gnomad AFR exome

AF:

0.0182

Gnomad AMR exome

AF:

0.0114

Gnomad ASJ exome

AF:

0.00172

Gnomad EAS exome

AF:

0.00683

Gnomad FIN exome

AF:

0.00232

Gnomad NFE exome

AF:

0.00248

Gnomad OTH exome

AF:

0.00185

GnomAD4 exome

AF:

0.00237

AC:

3343

AN:

1412576

Hom.:

Cov.:

AF XY:

0.00240

AC XY:

1692

AN XY:

703904

show subpopulations

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

African (AFR)

AF:

0.0126

AC:

372

AN:

29638

American (AMR)

AF:

0.00958

AC:

395

AN:

41252

Ashkenazi Jewish (ASJ)

AF:

0.00194

AC:

AN:

25744

East Asian (EAS)

AF:

0.00273

AC:

105

AN:

38510

South Asian (SAS)

AF:

0.00464

AC:

392

AN:

84518

European-Finnish (FIN)

AF:

0.00234

AC:

122

AN:

52200

Middle Eastern (MID)

AF:

0.00395

AC:

AN:

5566

European-Non Finnish (NFE)

AF:

0.00159

AC:

1713

AN:

1076504

Other (OTH)

AF:

0.00293

AC:

172

AN:

58644

⚠️ 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: 0.344

Heterozygous variant carriers

230

460

689

919

1149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

252

336

420

<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:

0.00533

AC:

792

AN:

148592

Hom.:

Cov.:

AF XY:

0.00559

AC XY:

406

AN XY:

72594

show subpopulations

African (AFR)

AF:

0.0136

AC:

541

AN:

39702

American (AMR)

AF:

0.00379

AC:

AN:

14766

Ashkenazi Jewish (ASJ)

AF:

0.00203

AC:

AN:

3442

East Asian (EAS)

AF:

0.00300

AC:

AN:

4996

South Asian (SAS)

AF:

0.00716

AC:

AN:

4746

European-Finnish (FIN)

AF:

0.00193

AC:

AN:

10374

Middle Eastern (MID)

AF:

0.0104

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00156

AC:

105

AN:

67320

Other (OTH)

AF:

0.00390

AC:

AN:

2052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.411

Heterozygous variant carriers

103

137

171

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00341

Hom.:

ExAC

AF:

0.0385

AC:

4679

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

Jan 15, 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

0.11

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.56

CADD

Benign

4.7

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0020

LIST_S2

Benign

0.52

T;T

MetaRNN

Benign

0.0040

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;.

PhyloP100

0.14

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-2.2

N;N

REVEL

Benign

0.077

Sift

Benign

0.17

T;T

Sift4G

Benign

0.23

T;.

Vest4

0.030

ClinPred

0.010

GERP RS

-4.9

Varity_R

0.19

gMVP

0.32

Mutation Taster

=87/13

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