rs1064424

Positions:

• chr22-23573515-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_020070.4(IGLL1):​c.393T>C​(p.Ala131=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,609,380 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (4 hom.)
• Consequence: IGLL1 NM_020070.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.35

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 22-23573515-A-G is Benign according to our data. Variant chr22-23573515-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 538829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-23573515-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.35 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGLL1	NM_020070.4	c.393T>C	p.Ala131=	synonymous_variant	3/3	ENST00000330377.3
IGLL1	NM_001369906.1	c.396T>C	p.Ala132=	synonymous_variant	3/3
IGLL1	NM_152855.3	c.*22T>C		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGLL1	ENST00000330377.3	c.393T>C	p.Ala131=	synonymous_variant	3/3	1	NM_020070.4	P1
IGLL1	ENST00000249053.3	c.*22T>C		3_prime_UTR_variant	2/2	1
IGLL1	ENST00000438703.1	c.396T>C	p.Ala132=	synonymous_variant	3/3	2
	ENST00000458318.2			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00184 AC: 280 AN: 151852 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000533

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00225

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00168 AC: 420 AN: 250272 Hom.: 1 AF XY: 0.00159 AC XY: 215 AN XY: 135280

Gnomad AFR exome AF: 0.000620

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.0149

Gnomad EAS exome AF: 0.00201

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00128

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00184 AC: 2683 AN: 1457412 Hom.: 4 Cov.: 33 AF XY: 0.00183 AC XY: 1327 AN XY: 725086

Gnomad4 AFR exome AF: 0.000630

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.0163

Gnomad4 EAS exome AF: 0.00239

Gnomad4 SAS exome AF: 0.000731

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00167

Gnomad4 OTH exome AF: 0.00266

GnomAD4 genome AF: 0.00186 AC: 282 AN: 151968 Hom.: 0 Cov.: 32 AF XY: 0.00180 AC XY: 134 AN XY: 74318

Gnomad4 AFR AF: 0.000531

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.0167

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00225

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00400 Hom.: 2

Bravo AF: 0.00183

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	IGLL1: BP4, BP7 -

Agammaglobulinemia 2, autosomal recessive Benign:1

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	-0.69
CADD	Benign	7.1
DANN	Benign	0.39

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: rs1064424; hg19: chr22-23915702;