NM_016734.3:c.964G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_016734.3(PAX5):c.964G>A(p.Ala322Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,611,354 control chromosomes in the GnomAD database, including 160 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0084 ( 9 hom., cov: 31)

Exomes 𝑓: 0.013 ( 151 hom. )

Consequence

PAX5
NM_016734.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 1.90

Publications

10 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0043126345).

BP6

Variant 9-36882052-C-T is Benign according to our data. Variant chr9-36882052-C-T is described in ClinVar as Benign. ClinVar VariationId is 135003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0084 (1279/152186) while in subpopulation NFE AF = 0.014 (950/67972). AF 95% confidence interval is 0.0132. There are 9 homozygotes in GnomAd4. There are 582 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX5	NM_016734.3 link	c.964G>A	p.Ala322Thr	missense_variant	Exon 8 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.964G>A	p.Ala322Thr	missense_variant	Exon 8 of 10	1	NM_016734.3	ENSP00000350844.4

Frequencies

GnomAD3 genomes

AF:

0.00841

AC:

1279

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00602

Gnomad ASJ

AF:

0.00835

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00498

Gnomad FIN

AF:

0.00386

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0140

Gnomad OTH

AF:

0.00575

GnomAD2 exomes

AF:

0.00970

AC:

2356

AN:

242998

AF XY:

0.00977

show subpopulations

Gnomad AFR exome

AF:

0.00309

Gnomad AMR exome

AF:

0.00766

Gnomad ASJ exome

AF:

0.00746

Gnomad EAS exome

AF:

0.000168

Gnomad FIN exome

AF:

0.00575

Gnomad NFE exome

AF:

0.0144

Gnomad OTH exome

AF:

0.0152

GnomAD4 exome

AF:

0.0132

AC:

19192

AN:

1459168

Hom.:

151

Cov.:

AF XY:

0.0129

AC XY:

9373

AN XY:

725630

show subpopulations

African (AFR)

AF:

0.00228

AC:

AN:

33370

American (AMR)

AF:

0.00788

AC:

351

AN:

44538

Ashkenazi Jewish (ASJ)

AF:

0.00745

AC:

194

AN:

26038

East Asian (EAS)

AF:

0.000127

AC:

AN:

39518

South Asian (SAS)

AF:

0.00582

AC:

501

AN:

86040

European-Finnish (FIN)

AF:

0.00559

AC:

298

AN:

53312

Middle Eastern (MID)

AF:

0.00209

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.0154

AC:

17103

AN:

1110356

Other (OTH)

AF:

0.0108

AC:

652

AN:

60248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

916

1831

2747

3662

4578

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

638

1276

1914

2552

3190

<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:

0.00840

AC:

1279

AN:

152186

Hom.:

Cov.:

AF XY:

0.00782

AC XY:

582

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.00313

AC:

130

AN:

41528

American (AMR)

AF:

0.00601

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00835

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00498

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00386

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0140

AC:

950

AN:

67972

Other (OTH)

AF:

0.00569

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

126

189

252

315

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0123

Hom.:

Bravo

AF:

0.00870

TwinsUK

AF:

0.0148

AC:

ALSPAC

AF:

0.0208

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0150

AC:

129

ExAC

AF:

0.00982

AC:

1192

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 10, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24728327) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1Other:1

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.063

T;.;.;T;.;T

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.82

T;T;T;T;T;T

MetaRNN

Benign

0.0043

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.3

N;N;.;.;.;.

PhyloP100

1.9

PrimateAI

Uncertain

0.69

PROVEAN

Benign

1.9

N;N;N;N;N;N

REVEL

Benign

0.078

Sift

Benign

1.0

T;T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T

Polyphen

0.047

B;.;.;.;.;B

Vest4

0.36

MVP

0.25

MPC

0.47

ClinPred

0.016

GERP RS

5.1

Varity_R

0.10

gMVP

0.36

Mutation Taster

=76/24

polymorphism

(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