rs142959335
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_020070.4(IGLL1):c.377T>C(p.Leu126Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000105 in 1,613,726 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: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
IGLL1
NM_020070.4 missense
NM_020070.4 missense
Scores
2
5
12
Clinical Significance
Conservation
PhyloP100: 3.70
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]
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ACMG classification
Classification made for transcript
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=0.0825679).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IGLL1 | NM_020070.4 | c.377T>C | p.Leu126Pro | missense_variant | 3/3 | ENST00000330377.3 | |
IGLL1 | NM_001369906.1 | c.380T>C | p.Leu127Pro | missense_variant | 3/3 | ||
IGLL1 | NM_152855.3 | c.*6T>C | 3_prime_UTR_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IGLL1 | ENST00000330377.3 | c.377T>C | p.Leu126Pro | missense_variant | 3/3 | 1 | NM_020070.4 | P1 | |
IGLL1 | ENST00000249053.3 | c.*6T>C | 3_prime_UTR_variant | 2/2 | 1 | ||||
IGLL1 | ENST00000438703.1 | c.380T>C | p.Leu127Pro | missense_variant | 3/3 | 2 | |||
ENST00000458318.2 | downstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000789 AC: 12AN: 152054Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000677 AC: 17AN: 251144Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135726
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GnomAD4 exome AF: 0.000107 AC: 157AN: 1461556Hom.: 0 Cov.: 33 AF XY: 0.000102 AC XY: 74AN XY: 727094
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GnomAD4 genome ? AF: 0.0000789 AC: 12AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74400
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 30, 2023 | The c.377T>C (p.L126P) alteration is located in exon 3 (coding exon 3) of the IGLL1 gene. This alteration results from a T to C substitution at nucleotide position 377, causing the leucine (L) at amino acid position 126 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Agammaglobulinemia 2, autosomal recessive Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 126 of the IGLL1 protein (p.Leu126Pro). This variant is present in population databases (rs142959335, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with IGLL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 569973). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Benign
Sift
Uncertain
D;D
Sift4G
Uncertain
D;.
Polyphen
B;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at