ENST00000523241.6:c.797G>A

Variant names:

• chr9-36846913-C-T
• rs35469494
• ENST00000523241.6:c.797G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000523241.6(PAX5):​c.797G>A​(p.Gly266Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0299 in 1,613,108 control chromosomes in the GnomAD database, including 852 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (56 hom., cov: 33)
  • Exomes 𝑓: 0.031 (796 hom.)
• Consequence: PAX5 ENST00000523241.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.374
• Publications: 11 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030234754).
• BP6: Variant 9-36846913-C-T is Benign according to our data. Variant chr9-36846913-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135004.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 = 0.0225 (3431/152322) while in subpopulation NFE AF = 0.0345 (2345/68022). AF 95% confidence interval is 0.0333. There are 56 homozygotes in GnomAd4. There are 1548 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 56 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000523241.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX5	NM_016734.3	MANE Select	c.1029G>A	p.Gly343Gly	synonymous	Exon 9 of 10	NP_057953.1
	PAX5	NM_001280549.2		c.797G>A	p.Gly266Glu	missense	Exon 7 of 8	NP_001267478.1
	PAX5	NM_001280547.2		c.927G>A	p.Gly309Gly	synonymous	Exon 8 of 9	NP_001267476.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX5	ENST00000523241.6	TSL:1	c.797G>A	p.Gly266Glu	missense	Exon 7 of 8	ENSP00000429637.1
	PAX5	ENST00000358127.9	TSL:1 MANE Select	c.1029G>A	p.Gly343Gly	synonymous	Exon 9 of 10	ENSP00000350844.4
	PAX5	ENST00000377852.7	TSL:1	c.927G>A	p.Gly309Gly	synonymous	Exon 8 of 9	ENSP00000367083.2

Frequencies

GnomAD3 genomes AF: 0.0226 AC: 3434 AN: 152204 Hom.: 56 Cov.: 33

Gnomad AFR AF: 0.00514

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.0207

Gnomad ASJ AF: 0.0276

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.0218

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0345

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0241 AC: 6049 AN: 251232 AF XY: 0.0244

Gnomad AFR exome AF: 0.00573

Gnomad AMR exome AF: 0.0134

Gnomad ASJ exome AF: 0.0264

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0222

Gnomad NFE exome AF: 0.0361

Gnomad OTH exome AF: 0.0263

GnomAD4 exome AF: 0.0306 AC: 44738 AN: 1460786 Hom.: 796 Cov.: 30 AF XY: 0.0302 AC XY: 21940 AN XY: 726746

African (AFR) AF: 0.00499 AC: 167 AN: 33470

American (AMR) AF: 0.0133 AC: 596 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0286 AC: 747 AN: 26126

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.0155 AC: 1338 AN: 86226

European-Finnish (FIN) AF: 0.0247 AC: 1320 AN: 53404

Middle Eastern (MID) AF: 0.0428 AC: 247 AN: 5768

European-Non Finnish (NFE) AF: 0.0347 AC: 38592 AN: 1111050

Other (OTH) AF: 0.0287 AC: 1729 AN: 60334

GnomAD4 genome AF: 0.0225 AC: 3431 AN: 152322 Hom.: 56 Cov.: 33 AF XY: 0.0208 AC XY: 1548 AN XY: 74484

African (AFR) AF: 0.00510 AC: 212 AN: 41582

American (AMR) AF: 0.0207 AC: 317 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0276 AC: 96 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0168 AC: 81 AN: 4830

European-Finnish (FIN) AF: 0.0218 AC: 231 AN: 10612

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0345 AC: 2345 AN: 68022

Other (OTH) AF: 0.0194 AC: 41 AN: 2114

Alfa AF: 0.0269 Hom.: 53

Bravo AF: 0.0214

TwinsUK AF: 0.0372 AC: 138

ALSPAC AF: 0.0355 AC: 137

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.0377 AC: 324

ExAC AF: 0.0249 AC: 3018

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.0343

EpiControl AF: 0.0354

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 19, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	6.5
DANN	Benign	0.94
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.30	T
PhyloP100		-0.37
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.38
Sift	Benign	0.15	T
Sift4G	Uncertain	0.050	T
Polyphen		0.0	B
Vest4		0.54
ClinPred		0.011	T
GERP RS		-0.41
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35469494; hg19: chr9-36846910;