rs116275804

Positions:

• chr22-23575013-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020070.4(IGLL1):​c.276C>T​(p.Asn92Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,610,684 control chromosomes in the GnomAD database, including 310 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (97 hom., cov: 32)
  • Exomes 𝑓: 0.013 (213 hom.)
• Consequence: IGLL1 NM_020070.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.24

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 22-23575013-G-A is Benign according to our data. Variant chr22-23575013-G-A is described in ClinVar as [Benign]. Clinvar id is 471475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-23575013-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGLL1	NM_020070.4	c.276C>T	p.Asn92Asn	synonymous_variant	2/3	ENST00000330377.3	NP_064455.1
IGLL1	NM_001369906.1	c.279C>T	p.Asn93Asn	synonymous_variant	2/3		NP_001356835.1
IGLL1	NM_152855.3	c.207-1428C>T		intron_variant			NP_690594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGLL1	ENST00000330377.3	c.276C>T	p.Asn92Asn	synonymous_variant	2/3	1	NM_020070.4	ENSP00000329312.2
IGLL1	ENST00000249053.3	c.207-1428C>T		intron_variant		1		ENSP00000249053.3
IGLL1	ENST00000438703.1	c.279C>T	p.Asn93Asn	synonymous_variant	2/3	2		ENSP00000403391.1

Frequencies

GnomAD3 genomes AF: 0.0249 AC: 3781 AN: 152152 Hom.: 96 Cov.: 32

Gnomad AFR AF: 0.0588

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0209

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.0125

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.0239

GnomAD3 exomes AF: 0.0150 AC: 3762 AN: 251372 Hom.: 57 AF XY: 0.0141 AC XY: 1914 AN XY: 135892

Gnomad AFR exome AF: 0.0576

Gnomad AMR exome AF: 0.0181

Gnomad ASJ exome AF: 0.0116

Gnomad EAS exome AF: 0.0109

Gnomad SAS exome AF: 0.0150

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.0182

GnomAD4 exome AF: 0.0126 AC: 18399 AN: 1458414 Hom.: 213 Cov.: 31 AF XY: 0.0124 AC XY: 8974 AN XY: 725676

Gnomad4 AFR exome AF: 0.0595

Gnomad4 AMR exome AF: 0.0189

Gnomad4 ASJ exome AF: 0.0105

Gnomad4 EAS exome AF: 0.0148

Gnomad4 SAS exome AF: 0.0134

Gnomad4 FIN exome AF: 0.00161

Gnomad4 NFE exome AF: 0.0113

Gnomad4 OTH exome AF: 0.0155

GnomAD4 genome AF: 0.0249 AC: 3792 AN: 152270 Hom.: 97 Cov.: 32 AF XY: 0.0232 AC XY: 1726 AN XY: 74468

Gnomad4 AFR AF: 0.0587

Gnomad4 AMR AF: 0.0209

Gnomad4 ASJ AF: 0.00835

Gnomad4 EAS AF: 0.0126

Gnomad4 SAS AF: 0.0141

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.0113

Gnomad4 OTH AF: 0.0274

Alfa AF: 0.0184 Hom.: 27

Bravo AF: 0.0288

EpiCase AF: 0.0104

EpiControl AF: 0.00990

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2021	- -

Agammaglobulinemia 2, autosomal recessive Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.55
DANN	Benign	0.80

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

LitVar

Other links and lift over

dbSNP: rs116275804; hg19: chr22-23917200; COSMIC: COSV50770256; COSMIC: COSV50770256;