rs35077960

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.923C>T(p.Ala308Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000754 in 1,595,034 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A308T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0042 ( 10 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 2 hom. )

Consequence

PAX5
NM_016734.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 7.75

Publications

4 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=0.008671492).

BP6

Variant 9-36882093-G-A is Benign according to our data. Variant chr9-36882093-G-A is described in ClinVar as Benign. ClinVar VariationId is 436163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00418 (636/152278) while in subpopulation AFR AF = 0.015 (623/41538). AF 95% confidence interval is 0.014. There are 10 homozygotes in GnomAd4. There are 323 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX5	NM_016734.3 link	c.923C>T	p.Ala308Val	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.923C>T	p.Ala308Val	missense_variant	Exon 8 of 10	1	NM_016734.3	ENSP00000350844.4

Frequencies

GnomAD3 genomes

AF:

0.00416

AC:

633

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000959

GnomAD2 exomes

AF:

0.000855

AC:

201

AN:

235126

AF XY:

0.000557

show subpopulations

Gnomad AFR exome

AF:

0.0122

Gnomad AMR exome

AF:

0.000220

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000572

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000353

GnomAD4 exome

AF:

0.000393

AC:

567

AN:

1442756

Hom.:

Cov.:

AF XY:

0.000328

AC XY:

235

AN XY:

715438

show subpopulations

African (AFR)

AF:

0.0144

AC:

473

AN:

32776

American (AMR)

AF:

0.000468

AC:

AN:

42702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25310

East Asian (EAS)

AF:

0.0000257

AC:

AN:

38978

South Asian (SAS)

AF:

0.0000473

AC:

AN:

84496

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52940

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.0000109

AC:

AN:

1100448

Other (OTH)

AF:

0.000943

AC:

AN:

59416

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00418

AC:

636

AN:

152278

Hom.:

Cov.:

AF XY:

0.00434

AC XY:

323

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0150

AC:

623

AN:

41538

American (AMR)

AF:

0.000653

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.000949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

126

157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00157

Hom.:

Bravo

AF:

0.00429

ESP6500AA

AF:

0.0111

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00105

AC:

127

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Nov 14, 2016

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;.;.;T;.;T

Eigen

Uncertain

0.61

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D;D;D

MetaRNN

Benign

0.0087

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;L;.;.;.;.

PhyloP100

7.8

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.5

N;N;N;N;N;N

REVEL

Benign

0.18

Sift

Benign

0.31

T;T;T;T;T;T

Sift4G

Benign

0.24

T;T;T;T;T;T

Polyphen

0.97

D;.;.;.;.;D

Vest4

0.89

MVP

0.46

MPC

0.52

ClinPred

0.021

GERP RS

6.0

Varity_R

0.16

gMVP

0.62

Mutation Taster

=16/84

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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