rs112775194

Positions:

chr22-23573471-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_020070.4(IGLL1):c.437C>T(p.Thr146Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000822 in 1,457,490 control chromosomes in the GnomAD database, including 4 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00082 ( 4 hom. )

Failed GnomAD Quality Control

Consequence

IGLL1
NM_020070.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.0410

Variant links:

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]

IGLL1 links:

ENSG00000224277 (HGNC:):

ENSG00000224277 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016934574).

BP6

Variant 22-23573471-G-A is Benign according to our data. Variant chr22-23573471-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547919.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}. Variant chr22-23573471-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGLL1	NM_020070.4 linkuse as main transcript	c.437C>T	p.Thr146Met	missense_variant	3/3	ENST00000330377.3	NP_064455.1	P15814-1
IGLL1	NM_001369906.1 linkuse as main transcript	c.440C>T	p.Thr147Met	missense_variant	3/3		NP_001356835.1
IGLL1	NM_152855.3 linkuse as main transcript	c.*66C>T		3_prime_UTR_variant	2/2		NP_690594.1	P15814-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
IGLL1	ENST00000330377.3 linkuse as main transcript	c.437C>T	p.Thr146Met	missense_variant	3/3	1	NM_020070.4	ENSP00000329312.2	P15814-1
IGLL1	ENST00000249053.3 linkuse as main transcript	c.*66C>T		3_prime_UTR_variant	2/2	1		ENSP00000249053.3	P15814-2
IGLL1	ENST00000438703.1 linkuse as main transcript	c.440C>T	p.Thr147Met	missense_variant	3/3	2		ENSP00000403391.1	C9JEE0
ENSG00000224277	ENST00000458318.2 linkuse as main transcript	n.397G>A		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

173

AN:

151764

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.000604

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000866

Gnomad EAS

AF:

0.00501

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00143

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.00106

AC:

267

AN:

251096

Hom.:

AF XY:

0.00118

AC XY:

160

AN XY:

135698

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.00424

Gnomad SAS exome

AF:

0.00271

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000573

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000822

AC:

1198

AN:

1457490

Hom.:

Cov.:

AF XY:

0.000885

AC XY:

642

AN XY:

725050

show subpopulations

Gnomad4 AFR exome

AF:

0.000658

Gnomad4 AMR exome

AF:

0.000448

Gnomad4 ASJ exome

AF:

0.00145

Gnomad4 EAS exome

AF:

0.00315

Gnomad4 SAS exome

AF:

0.00291

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.000598

Gnomad4 OTH exome

AF:

0.000997

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00115

AC:

175

AN:

151882

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.000650

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.000866

Gnomad4 EAS

AF:

0.00503

Gnomad4 SAS

AF:

0.00332

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00143

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.00100

Hom.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00119

AC:

145

EpiCase

AF:

0.000764

EpiControl

AF:

0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Agammaglobulinemia 2, autosomal recessive

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	The IGLL1 c.437C>T, p.Thr146Met variant (rs112775194), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 547919). This variant is found in the East Asian population with an allele frequency of 0.5% (91/19,954 alleles) in the Genome Aggregation Database. The threonine at codon 146 is weakly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Thr146Met variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 10, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

IGLL1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.27

T;.

Eigen

Benign

-0.92

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0077

LIST_S2

Benign

0.36

T;T

M_CAP

Benign

0.0047

MetaRNN

Benign

0.017

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;.

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.7

D;D

REVEL

Benign

0.065

Sift

Uncertain

0.024

D;D

Sift4G

Uncertain

0.023

D;.

Polyphen

0.84

P;.

Vest4

0.12

MVP

0.21

MPC

0.16

ClinPred

0.082

GERP RS

-1.7

Varity_R

0.13

gMVP

0.36

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over