22-23573183-G-A

Variant names:

• chr22-23573183-G-A
• rs8141940
• NM_020070.4:c.*83C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020070.4(IGLL1):​c.*83C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0549 in 1,310,578 control chromosomes in the GnomAD database, including 4,108 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.11 (1734 hom., cov: 32)
  • Exomes 𝑓: 0.048 (2374 hom.)
• Consequence: IGLL1 NM_020070.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.867
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGLL1	NM_020070.4	c.*83C>T		3_prime_UTR_variant	Exon 3 of 3	ENST00000330377.3	NP_064455.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGLL1	ENST00000330377.3	c.*83C>T		3_prime_UTR_variant	Exon 3 of 3	1	NM_020070.4	ENSP00000329312.2

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16737 AN: 152052 Hom.: 1727 Cov.: 32

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0551

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.0537

Gnomad FIN AF: 0.0544

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0411

Gnomad OTH AF: 0.102

GnomAD4 exome AF: 0.0476 AC: 55151 AN: 1158408 Hom.: 2374 Cov.: 16 AF XY: 0.0477 AC XY: 28149 AN XY: 590446

African (AFR) AF: 0.286 AC: 7798 AN: 27292

American (AMR) AF: 0.0403 AC: 1750 AN: 43388

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 2815 AN: 23634

East Asian (EAS) AF: 0.00998 AC: 383 AN: 38374

South Asian (SAS) AF: 0.0541 AC: 4296 AN: 79436

European-Finnish (FIN) AF: 0.0505 AC: 2669 AN: 52872

Middle Eastern (MID) AF: 0.107 AC: 437 AN: 4090

European-Non Finnish (NFE) AF: 0.0378 AC: 31718 AN: 839146

Other (OTH) AF: 0.0655 AC: 3285 AN: 50176

GnomAD4 genome AF: 0.110 AC: 16777 AN: 152170 Hom.: 1734 Cov.: 32 AF XY: 0.108 AC XY: 8055 AN XY: 74414

African (AFR) AF: 0.280 AC: 11595 AN: 41464

American (AMR) AF: 0.0550 AC: 842 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 389 AN: 3468

East Asian (EAS) AF: 0.0108 AC: 56 AN: 5170

South Asian (SAS) AF: 0.0533 AC: 257 AN: 4820

European-Finnish (FIN) AF: 0.0544 AC: 578 AN: 10616

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0411 AC: 2793 AN: 68014

Other (OTH) AF: 0.101 AC: 213 AN: 2110

Alfa AF: 0.0829 Hom.: 390

Bravo AF: 0.118

Asia WGS AF: 0.0560 AC: 195 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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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
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.5
DANN	Benign	0.49
PhyloP100		0.87
Mutation Taster		=99/1	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: rs8141940; hg19: chr22-23915370; COSMIC: COSV50770124; COSMIC: COSV50770124;