rs137870876

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_016734.3(PAX5):c.638C>T(p.Ser213Leu) variant causes a missense change. The variant allele was found at a frequency of 0.001 in 1,614,082 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. S213S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 2 hom. )

Consequence

PAX5
NM_016734.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2O:1

Conservation

PhyloP100: 5.66

Publications

13 publications found

Variant links:

Genes affected

PAX5 (HGNC:8619): (paired box 5) This gene encodes a member of the paired box (PAX) family of transcription factors. The central feature of this gene family is a novel, highly conserved DNA-binding motif, known as the paired box. Paired box transcription factors are important regulators in early development, and alterations in the expression of their genes are thought to contribute to neoplastic transformation. This gene encodes the B-cell lineage specific activator protein that is expressed at early, but not late stages of B-cell differentiation. Its expression has also been detected in developing CNS and testis and so the encoded protein may also play a role in neural development and spermatogenesis. This gene is located at 9p13, which is involved in t(9;14)(p13;q32) translocations recurring in small lymphocytic lymphomas of the plasmacytoid subtype, and in derived large-cell lymphomas. This translocation brings the potent E-mu enhancer of the IgH gene into close proximity of the PAX5 promoter, suggesting that the deregulation of transcription of this gene contributes to the pathogenesis of these lymphomas. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

PAX5 Gene-Disease associations (from GenCC):

leukemia, acute lymphoblastic, susceptibility to, 3
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
neurodevelopmental disorder
Inheritance: AD Classification: MODERATE Submitted by: Broad Center for Mendelian Genomics
PAX5-related B lymphopenia and autism spectrum disorder
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

PAX5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25095463).

BP6

Variant 9-36966691-G-A is Benign according to our data. Variant chr9-36966691-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135001.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000604 (92/152226) while in subpopulation NFE AF = 0.00115 (78/68032). AF 95% confidence interval is 0.000941. There are 0 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX5	NM_016734.3 link	c.638C>T	p.Ser213Leu	missense_variant	Exon 6 of 10	ENST00000358127.9	NP_057953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX5	ENST00000358127.9 link	c.638C>T	p.Ser213Leu	missense_variant	Exon 6 of 10	1	NM_016734.3	ENSP00000350844.4

Frequencies

GnomAD3 genomes

AF:

0.000604

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00115

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000621

AC:

156

AN:

251306

AF XY:

0.000545

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00114

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.00104

AC:

1525

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00100

AC XY:

729

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33478

American (AMR)

AF:

0.000268

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000336

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000936

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00128

AC:

1421

AN:

1111992

Other (OTH)

AF:

0.000828

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

155

232

310

387

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000604

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.000444

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41456

American (AMR)

AF:

0.000131

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.000414

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00115

AC:

AN:

68032

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000858

Hom.:

Bravo

AF:

0.000638

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000659

AC:

EpiCase

AF:

0.00136

EpiControl

AF:

0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 19, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24728327) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 24, 2021

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1Other:1

Jul 08, 2021

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA sequence analysis of the PAX5 gene demonstrated a sequence change, c.638C>T, in exon 6 that results in an amino acid change, p.Ser213Leu. This sequence change does not appear to have been previously described in patients with PAX5-related disorders and has been described in the gnomAD database with a frequency of 0.11% in the European sub-population (dbSNP rs137870876). The p.Ser213Leu change affects a highly conserved amino acid residue located in a domain of the PAX5 protein that is not known to be functional. The p.Ser213Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to the lack of functional studies, the clinical significance of the p.Ser213Leu change remains unknown at this time. -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Leukemia, acute lymphoblastic, susceptibility to, 3

Benign:1

Feb 11, 2021

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PAX5 c.638C>T (p.Ser213Leu) missense change has a maximum subpopulation frequency of 0.11% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/9-36966688-G-A?dataset=gnomad_r2_1). This population frequency is higher than expected for a pathogenic variant in PAX5 causing predisposition to acute lymphoblastic leukemia (BS1). In silico tools are not in agreement about the effect on the gene or protein function and functional studies have not been performed. This variant has been identified in patients without a personal or family history of acute lymphoblastic leukemia (internal data). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.028

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

D;.;.;.;.;.;.;T;T;.;.;T

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.97

D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.29

MetaRNN

Benign

0.25

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.2

M;M;M;.;.;.;.;.;.;.;M;.

PhyloP100

5.7

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-4.1

D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Uncertain

0.60

Sift

Uncertain

0.0060

D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.049

D;D;T;T;D;D;D;T;D;D;T;D

Polyphen

0.46

P;.;.;P;P;.;.;.;.;.;.;.

Vest4

0.42

MVP

0.91

MPC

0.91

ClinPred

0.079

GERP RS

5.5

Varity_R

0.29

gMVP

0.59

Mutation Taster

=30/70

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over