rs34810717

Positions:

chr9-36882052-C-T

Variant summary

Our verdict is Benign. Variant got -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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

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

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 links:

PAX5 (HGNC:):

PAX5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 135003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36882052-C-T is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1279 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX5	NM_016734.3 linkuse as main transcript	c.964G>A	p.Ala322Thr	missense_variant	8/10	ENST00000358127.9	NP_057953.1	Q02548-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX5	ENST00000358127.9 linkuse as main transcript	c.964G>A	p.Ala322Thr	missense_variant	8/10	1	NM_016734.3	ENSP00000350844.4		Q02548-1

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

GnomAD3 exomes

AF:

0.00970

AC:

2356

AN:

242998

Hom.:

AF XY:

0.00977

AC XY:

1288

AN XY:

131828

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 SAS exome

AF:

0.00606

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

Gnomad4 AFR exome

AF:

0.00228

Gnomad4 AMR exome

AF:

0.00788

Gnomad4 ASJ exome

AF:

0.00745

Gnomad4 EAS exome

AF:

0.000127

Gnomad4 SAS exome

AF:

0.00582

Gnomad4 FIN exome

AF:

0.00559

Gnomad4 NFE exome

AF:

0.0154

Gnomad4 OTH exome

AF:

0.0108

GnomAD4 genome

AF:

0.00840

AC:

1279

AN:

152186

Hom.:

Cov.:

AF XY:

0.00782

AC XY:

582

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.00313

Gnomad4 AMR

AF:

0.00601

Gnomad4 ASJ

AF:

0.00835

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00498

Gnomad4 FIN

AF:

0.00386

Gnomad4 NFE

AF:

0.0140

Gnomad4 OTH

AF:

0.00569

Alfa

AF:

0.0128

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2021	This variant is associated with the following publications: (PMID: 24728327) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:1Other:1

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

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

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;.;.;.;.

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

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