chr22-23573292-T-A

Position:

chr22-23573292-T-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_020070.4(IGLL1):c.616A>T(p.Thr206Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000806 in 1,613,876 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. T206T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00078 ( 1 hom. )

Consequence

IGLL1
NM_020070.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0920

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.012562066).

BP6

Variant 22-23573292-T-A is Benign according to our data. Variant chr22-23573292-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 439824.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGLL1	NM_020070.4 linkuse as main transcript	c.616A>T	p.Thr206Ser	missense_variant	3/3	ENST00000330377.3	NP_064455.1	P15814-1
IGLL1	NM_001369906.1 linkuse as main transcript	c.619A>T	p.Thr207Ser	missense_variant	3/3		NP_001356835.1
IGLL1	NM_152855.3 linkuse as main transcript	c.*245A>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.616A>T	p.Thr206Ser	missense_variant	3/3	1	NM_020070.4	ENSP00000329312.2	P15814-1
IGLL1	ENST00000249053.3 linkuse as main transcript	c.*245A>T		3_prime_UTR_variant	2/2	1		ENSP00000249053.3	P15814-2
ENSG00000224277	ENST00000458318.2 linkuse as main transcript	n.391-173T>A		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00102

AC:

155

AN:

151972

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00531

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000809

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000688

AC:

173

AN:

251434

Hom.:

AF XY:

0.000581

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000870

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.000784

AC:

1146

AN:

1461784

Hom.:

Cov.:

AF XY:

0.000765

AC XY:

556

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00148

Gnomad4 ASJ exome

AF:

0.000650

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.000875

Gnomad4 OTH exome

AF:

0.000762

GnomAD4 genome

AF:

0.00102

AC:

155

AN:

152092

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.00530

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.000388

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000809

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000893

Hom.:

Bravo

AF:

0.00110

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000552

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000652

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:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 20, 2023	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 206 of the IGLL1 protein (p.Thr206Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 439824). 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 tolerated. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jul 09, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 24, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.77

CADD

Benign

8.5

DANN

Benign

0.74

DEOGEN2

Benign

0.29

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.087

LIST_S2

Benign

0.57

M_CAP

Benign

0.0092

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.25

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.051

Sift

Benign

0.23

Sift4G

Benign

0.41

Polyphen

0.023

Vest4

0.059

MVP

0.12

MPC

0.049

ClinPred

0.0045

GERP RS

1.2

Varity_R

0.16

gMVP

0.22

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