NM_016734.3:c.244G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM1BP4_StrongBP6_Very_StrongBS1

The NM_016734.3(PAX5):c.244G>A(p.Val82Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

PAX5
NM_016734.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: 7.91

Publications

6 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 -14 ACMG points.

PM1

In a DNA_binding_region Paired (size 126) in uniprot entity PAX5_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_016734.3

BP4

Computational evidence support a benign effect (MetaRNN=0.017112374).

BP6

Variant 9-37015163-C-T is Benign according to our data. Variant chr9-37015163-C-T is described in CliVar as Benign. Clinvar id is 134999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-37015163-C-T is described in CliVar as Benign. Clinvar id is 134999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-37015163-C-T is described in CliVar as Benign. Clinvar id is 134999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-37015163-C-T is described in CliVar as Benign. Clinvar id is 134999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-37015163-C-T is described in CliVar as Benign. Clinvar id is 134999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-37015163-C-T is described in CliVar as Benign. Clinvar id is 134999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-37015163-C-T is described in CliVar as Benign. Clinvar id is 134999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-37015163-C-T is described in CliVar as Benign. Clinvar id is 134999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-37015163-C-T is described in CliVar as Benign. Clinvar id is 134999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-37015163-C-T is described in CliVar as Benign. Clinvar id is 134999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-37015163-C-T is described in CliVar as Benign. Clinvar id is 134999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-37015163-C-T is described in CliVar as Benign. Clinvar id is 134999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-37015163-C-T is described in CliVar as Benign. Clinvar id is 134999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-37015163-C-T is described in CliVar as Benign. Clinvar id is 134999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-37015163-C-T is described in CliVar as Benign. Clinvar id is 134999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-37015163-C-T is described in CliVar as Benign. Clinvar id is 134999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-37015163-C-T is described in CliVar as Benign. Clinvar id is 134999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-37015163-C-T is described in CliVar as Benign. Clinvar id is 134999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000105 (16/152192) while in subpopulation AMR AF = 0.00105 (16/15274). AF 95% confidence interval is 0.000657. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX5	NM_016734.3 link	c.244G>A	p.Val82Ile	missense_variant	Exon 3 of 10	ENST00000358127.9	NP_057953.1	Q02548-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX5	ENST00000358127.9 link	c.244G>A	p.Val82Ile	missense_variant	Exon 3 of 10	1	NM_016734.3	ENSP00000350844.4		Q02548-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000915

AC:

230

AN:

251484

AF XY:

0.000589

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00659

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000168

AC:

246

AN:

1461832

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00546

AC:

244

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111958

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000105

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00105

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

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:

0.000183

Hom.:

Bravo

AF:

0.000404

ExAC

AF:

0.000700

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1Other:1

Mar 10, 2021

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

not provided

Benign:1

Nov 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

D;.;.;.;.;.;.;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

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

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.017

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

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

PhyloP100

7.9

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.86

N;N;N;N;N;N;N;N

REVEL

Pathogenic

0.67

Sift

Benign

0.031

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

Sift4G

Uncertain

0.048

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

Polyphen

0.66

P;.;.;B;P;.;.;.

Vest4

0.40

MutPred

0.67

Loss of ubiquitination at K79 (P = 0.1647);Loss of ubiquitination at K79 (P = 0.1647);Loss of ubiquitination at K79 (P = 0.1647);Loss of ubiquitination at K79 (P = 0.1647);Loss of ubiquitination at K79 (P = 0.1647);Loss of ubiquitination at K79 (P = 0.1647);Loss of ubiquitination at K79 (P = 0.1647);Loss of ubiquitination at K79 (P = 0.1647);

MVP

0.90

MPC

2.2

ClinPred

0.14

GERP RS

5.7

Varity_R

0.46

gMVP

0.80

Mutation Taster

=195/105

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