22-23573574-C-T

Position:

chr22-23573574-C-T

Variant summary

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

The NM_020070.4(IGLL1):c.334G>A(p.Ala112Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,612,964 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A112A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0012 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 1 hom. )

Consequence

IGLL1
NM_020070.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.232

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006251365).

BP6

Variant 22-23573574-C-T is Benign according to our data. Variant chr22-23573574-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 538828.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}. Variant chr22-23573574-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
IGLL1	NM_020070.4 linkuse as main transcript	c.334G>A	p.Ala112Thr	missense_variant	3/3	ENST00000330377.3	NP_064455.1
IGLL1	NM_001369906.1 linkuse as main transcript	c.337G>A	p.Ala113Thr	missense_variant	3/3		NP_001356835.1
IGLL1	NM_152855.3 linkuse as main transcript	c.218G>A	p.Gly73Asp	missense_variant	2/2		NP_690594.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGLL1	ENST00000330377.3 linkuse as main transcript	c.334G>A	p.Ala112Thr	missense_variant	3/3	1	NM_020070.4	ENSP00000329312	P1	P15814-1
IGLL1	ENST00000249053.3 linkuse as main transcript	c.218G>A	p.Gly73Asp	missense_variant	2/2	1		ENSP00000249053		P15814-2
IGLL1	ENST00000438703.1 linkuse as main transcript	c.337G>A	p.Ala113Thr	missense_variant	3/3	2		ENSP00000403391

Frequencies

GnomAD3 genomes

AF:

0.00117

AC:

177

AN:

151678

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000561

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00347

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00156

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000912

AC:

229

AN:

251048

Hom.:

AF XY:

0.000840

AC XY:

114

AN XY:

135682

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.000497

Gnomad EAS exome

AF:

0.00277

Gnomad SAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.000944

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00141

AC:

2064

AN:

1461168

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

995

AN XY:

726908

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.00229

Gnomad4 SAS exome

AF:

0.000429

Gnomad4 FIN exome

AF:

0.00124

Gnomad4 NFE exome

AF:

0.00151

Gnomad4 OTH exome

AF:

0.00250

GnomAD4 genome

AF:

0.00120

AC:

182

AN:

151796

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

AN XY:

74212

show subpopulations

Gnomad4 AFR

AF:

0.000559

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00348

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000660

Gnomad4 NFE

AF:

0.00156

Gnomad4 OTH

AF:

0.00285

Alfa

AF:

0.00106

Hom.:

Bravo

AF:

0.00118

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000939

AC:

114

EpiCase

AF:

0.00218

EpiControl

AF:

0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Agammaglobulinemia 2, autosomal recessive

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 06, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2021

The c.334G>A (p.A112T) alteration is located in exon 3 (coding exon 3) of the IGLL1 gene. This alteration results from a G to A substitution at nucleotide position 334, causing the alanine (A) at amino acid position 112 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Uncertain

0.58

D;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0029

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.0019

MetaRNN

Benign

0.0063

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.1

D;D

REVEL

Benign

0.014

Sift

Uncertain

0.0020

D;D

Sift4G

Benign

0.17

T;.

Polyphen

0.049

B;.

Vest4

0.036

MVP

0.10

MPC

0.059

ClinPred

0.012

GERP RS

-4.9

Varity_R

0.39

gMVP

0.20

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