22-23575005-G-T

Position:

chr22-23575005-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020070.4(IGLL1):c.284C>A(p.Thr95Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,610,198 control chromosomes in the GnomAD database, including 306 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 98 hom., cov: 32)

Exomes 𝑓: 0.012 ( 208 hom. )

Consequence

IGLL1
NM_020070.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.204

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027917027).

BP6

Variant 22-23575005-G-T is Benign according to our data. Variant chr22-23575005-G-T is described in ClinVar as [Benign]. Clinvar id is 471476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-23575005-G-T is described in Lovd as [Benign]. Variant chr22-23575005-G-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGLL1	NM_020070.4 link	c.284C>A	p.Thr95Lys	missense_variant	2/3	ENST00000330377.3	NP_064455.1	P15814-1
IGLL1	NM_001369906.1 link	c.287C>A	p.Thr96Lys	missense_variant	2/3		NP_001356835.1
IGLL1	NM_152855.3 link	c.207-1420C>A		intron_variant			NP_690594.1	P15814-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
IGLL1	ENST00000330377.3 link	c.284C>A	p.Thr95Lys	missense_variant	2/3	1	NM_020070.4	ENSP00000329312.2	P15814-1
IGLL1	ENST00000249053.3 link	c.207-1420C>A		intron_variant		1		ENSP00000249053.3	P15814-2
IGLL1	ENST00000438703.1 link	c.287C>A	p.Thr96Lys	missense_variant	2/3	2		ENSP00000403391.1	C9JEE0

Frequencies

GnomAD3 genomes

AF:

0.0249

AC:

3781

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0589

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0210

Gnomad ASJ

AF:

0.00835

Gnomad EAS

AF:

0.0125

Gnomad SAS

AF:

0.0141

Gnomad FIN

AF:

0.00169

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0113

Gnomad OTH

AF:

0.0239

GnomAD3 exomes

AF:

0.0149

AC:

3748

AN:

251362

Hom.:

AF XY:

0.0140

AC XY:

1897

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.0579

Gnomad AMR exome

AF:

0.0181

Gnomad ASJ exome

AF:

0.0116

Gnomad EAS exome

AF:

0.0109

Gnomad SAS exome

AF:

0.0144

Gnomad FIN exome

AF:

0.00152

Gnomad NFE exome

AF:

0.0113

Gnomad OTH exome

AF:

0.0181

GnomAD4 exome

AF:

0.0124

AC:

18127

AN:

1457950

Hom.:

208

Cov.:

AF XY:

0.0122

AC XY:

8854

AN XY:

725510

show subpopulations

Gnomad4 AFR exome

AF:

0.0585

Gnomad4 AMR exome

AF:

0.0189

Gnomad4 ASJ exome

AF:

0.0104

Gnomad4 EAS exome

AF:

0.0147

Gnomad4 SAS exome

AF:

0.0129

Gnomad4 FIN exome

AF:

0.00161

Gnomad4 NFE exome

AF:

0.0111

Gnomad4 OTH exome

AF:

0.0154

GnomAD4 genome

AF:

0.0249

AC:

3792

AN:

152248

Hom.:

Cov.:

AF XY:

0.0232

AC XY:

1728

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0588

Gnomad4 AMR

AF:

0.0210

Gnomad4 ASJ

AF:

0.00835

Gnomad4 EAS

AF:

0.0126

Gnomad4 SAS

AF:

0.0141

Gnomad4 FIN

AF:

0.00169

Gnomad4 NFE

AF:

0.0113

Gnomad4 OTH

AF:

0.0274

Alfa

AF:

0.0147

Hom.:

Bravo

AF:

0.0288

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.0143

AC:

ESP6500AA

AF:

0.0452

AC:

199

ESP6500EA

AF:

0.00791

AC:

ExAC

AF:

0.0164

AC:

1995

EpiCase

AF:

0.0104

EpiControl

AF:

0.00990

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2018	This variant is associated with the following publications: (PMID: 25363768) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Agammaglobulinemia 2, autosomal recessive

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.57

DANN

Benign

0.77

DEOGEN2

Benign

0.18

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0065

LIST_S2

Benign

0.063

T;T

MetaRNN

Benign

0.0028

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.0

N;.

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.020

N;N

REVEL

Benign

0.12

Sift

Benign

0.19

T;T

Sift4G

Benign

0.33

T;.

Polyphen

0.019

B;.

Vest4

0.068

MPC

0.060

ClinPred

0.0014

GERP RS

0.47

Varity_R

0.14

gMVP

0.25

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