22-23579994-C-A

Position:

• chr22-23579994-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020070.4(IGLL1):​c.197G>T​(p.Arg66Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IGLL1 NM_020070.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.03

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049106717).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGLL1	NM_020070.4	c.197G>T	p.Arg66Leu	missense_variant	1/3	ENST00000330377.3	NP_064455.1
IGLL1	NM_001369906.1	c.197G>T	p.Arg66Leu	missense_variant	1/3		NP_001356835.1
IGLL1	NM_152855.3	c.197G>T	p.Arg66Leu	missense_variant	1/2		NP_690594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGLL1	ENST00000330377.3	c.197G>T	p.Arg66Leu	missense_variant	1/3	1	NM_020070.4	ENSP00000329312.2
IGLL1	ENST00000249053.3	c.197G>T	p.Arg66Leu	missense_variant	1/2	1		ENSP00000249053.3
IGLL1	ENST00000438703.1	c.197G>T	p.Arg66Leu	missense_variant	1/3	2		ENSP00000403391.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1428904 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 708984

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Agammaglobulinemia 2, autosomal recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 15, 2019

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals with IGLL1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 66 of the IGLL1 protein (p.Arg66Leu). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	1.2
DANN	Benign	0.61
DEOGEN2	Benign	0.11	.;T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.24	T;T;T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.049	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.55	N;N;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.75	N;N;N
REVEL	Uncertain	0.40
Sift	Benign	0.49	T;T;T
Sift4G	Benign	0.42	T;T;.
Polyphen		0.0	.;B;.
Vest4		0.18
MutPred		0.35		Loss of sheet (P = 3e-04);Loss of sheet (P = 3e-04);Loss of sheet (P = 3e-04);
MVP		0.11
MPC		0.062
ClinPred		0.033	T
GERP RS		-1.6
Varity_R		0.035
gMVP		0.32

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: rs569884568; hg19: chr22-23922181; COSMIC: COSV50769902; COSMIC: COSV50769902;