rs139571703

Variant names:

• chr22-23573433-C-T
• rs139571703
• NM_020070.4:c.475G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020070.4(IGLL1):​c.475G>A​(p.Gly159Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.034 in 1,612,944 control chromosomes in the GnomAD database, including 951 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G159G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.031 (81 hom., cov: 32)
  • Exomes 𝑓: 0.034 (870 hom.)
• Consequence: IGLL1 NM_020070.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.10
• Publications: 10 publications found

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

ENSG00000224277 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010354221).
• BP6: Variant 22-23573433-C-T is Benign according to our data. Variant chr22-23573433-C-T is described in ClinVar as [Benign]. Clinvar id is 478784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0309 (4691/152048) while in subpopulation SAS AF = 0.0465 (224/4818). AF 95% confidence interval is 0.0415. There are 81 homozygotes in GnomAd4. There are 2281 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 81 Unknown,AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGLL1	NM_020070.4	c.475G>A	p.Gly159Ser	missense_variant	Exon 3 of 3	ENST00000330377.3	NP_064455.1
IGLL1	NM_001369906.1	c.478G>A	p.Gly160Ser	missense_variant	Exon 3 of 3		NP_001356835.1
IGLL1	NM_152855.3	c.*104G>A		3_prime_UTR_variant	Exon 2 of 2		NP_690594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGLL1	ENST00000330377.3	c.475G>A	p.Gly159Ser	missense_variant	Exon 3 of 3	1	NM_020070.4	ENSP00000329312.2
IGLL1	ENST00000249053.3	c.*104G>A		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000249053.3
IGLL1	ENST00000438703.1	c.478G>A	p.Gly160Ser	missense_variant	Exon 3 of 3	2		ENSP00000403391.1
ENSG00000224277	ENST00000458318.2	n.391-32C>T		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes AF: 0.0309 AC: 4692 AN: 151930 Hom.: 80 Cov.: 32

Gnomad AFR AF: 0.0258

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0217

Gnomad ASJ AF: 0.0300

Gnomad EAS AF: 0.0211

Gnomad SAS AF: 0.0467

Gnomad FIN AF: 0.0296

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0359

Gnomad OTH AF: 0.0321

GnomAD2 exomes AF: 0.0331 AC: 8304 AN: 251212 AF XY: 0.0341

Gnomad AFR exome AF: 0.0263

Gnomad AMR exome AF: 0.0187

Gnomad ASJ exome AF: 0.0323

Gnomad EAS exome AF: 0.0226

Gnomad FIN exome AF: 0.0344

Gnomad NFE exome AF: 0.0366

Gnomad OTH exome AF: 0.0352

GnomAD4 exome AF: 0.0343 AC: 50105 AN: 1460896 Hom.: 870 Cov.: 33 AF XY: 0.0351 AC XY: 25485 AN XY: 726790

African (AFR) AF: 0.0244 AC: 817 AN: 33468

American (AMR) AF: 0.0196 AC: 878 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0320 AC: 835 AN: 26130

East Asian (EAS) AF: 0.0156 AC: 619 AN: 39696

South Asian (SAS) AF: 0.0449 AC: 3876 AN: 86238

European-Finnish (FIN) AF: 0.0373 AC: 1992 AN: 53420

Middle Eastern (MID) AF: 0.0448 AC: 258 AN: 5762

European-Non Finnish (NFE) AF: 0.0349 AC: 38833 AN: 1111110

Other (OTH) AF: 0.0331 AC: 1997 AN: 60360

GnomAD4 genome AF: 0.0309 AC: 4691 AN: 152048 Hom.: 81 Cov.: 32 AF XY: 0.0307 AC XY: 2281 AN XY: 74322

African (AFR) AF: 0.0258 AC: 1069 AN: 41510

American (AMR) AF: 0.0216 AC: 331 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0300 AC: 104 AN: 3470

East Asian (EAS) AF: 0.0209 AC: 108 AN: 5156

South Asian (SAS) AF: 0.0465 AC: 224 AN: 4818

European-Finnish (FIN) AF: 0.0296 AC: 314 AN: 10602

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0359 AC: 2440 AN: 67886

Other (OTH) AF: 0.0313 AC: 66 AN: 2110

Alfa AF: 0.0355 Hom.: 34

Bravo AF: 0.0295

TwinsUK AF: 0.0291 AC: 108

ALSPAC AF: 0.0314 AC: 121

ESP6500AA AF: 0.0275 AC: 121

ESP6500EA AF: 0.0379 AC: 326

ExAC AF: 0.0338 AC: 4103

EpiCase AF: 0.0363

EpiControl AF: 0.0373

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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 01, 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	0.20
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.93	D;D
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.6	M;.
PhyloP100		3.1
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.051	T;.
Polyphen		0.61	P;.
Vest4		0.12
MPC		0.27
ClinPred		0.037	T
GERP RS		2.5
Varity_R		0.76
gMVP		0.51
Mutation Taster		=84/16	polymorphism (auto)

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

Other links and lift over

dbSNP: rs139571703; hg19: chr22-23915620; COSMIC: COSV50770446; COSMIC: COSV50770446;