22-23573289-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020070.4(IGLL1):c.619G>A(p.Val207Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: IGLL1 NM_020070.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.74

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23742986).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGLL1	NM_020070.4	c.619G>A	p.Val207Met	missense_variant	3/3	ENST00000330377.3
IGLL1	NM_001369906.1	c.622G>A	p.Val208Met	missense_variant	3/3
IGLL1	NM_152855.3	c.*248G>A		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGLL1	ENST00000330377.3	c.619G>A	p.Val207Met	missense_variant	3/3	1	NM_020070.4	P1
IGLL1	ENST00000249053.3	c.*248G>A		3_prime_UTR_variant	2/2	1
	ENST00000458318.2	n.391-176C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251438 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461870 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Invitae

Nov 01, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 947731). This variant has not been reported in the literature in individuals affected with IGLL1-related conditions. This variant is present in population databases (rs779159751, gnomAD 0.003%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 207 of the IGLL1 protein (p.Val207Met). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	13
Dann	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.030	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.031
Sift	Uncertain	0.022	D
Sift4G	Benign	0.063	T
Polyphen		0.90	P
Vest4		0.11
MutPred		0.60		Loss of sheet (P = 0.0181);
MVP		0.14
MPC		0.31
ClinPred		0.62	D
GERP RS		1.4
Varity_R		0.22
gMVP		0.35

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: rs779159751; hg19: chr22-23915476; COSMIC: COSV99968663; COSMIC: COSV99968663;