rs3780135

chr9-36840626-G-Achr9-36840626-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000523241.6(PAX5):c.878C>T(p.Thr293Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.91 in 1,570,902 control chromosomes in the GnomAD database, including 662,872 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (50582 hom., cov: 30)
  • Exomes 𝑓: 0.92 (612290 hom.)
• Consequence: PAX5 ENST00000523241.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.626

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.8845094E-7).
• BP6: Variant 9-36840626-G-A is Benign according to our data. Variant chr9-36840626-G-A is described in ClinVar as [Benign]. Clinvar id is 134998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.941 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX5	NM_016734.3	c.1110C>T	p.Tyr370=	synonymous_variant	10/10	ENST00000358127.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX5	ENST00000358127.9	c.1110C>T	p.Tyr370=	synonymous_variant	10/10	1	NM_016734.3	P1

Frequencies

GnomAD3 genomes AF: 0.778 AC: 118283 AN: 151938 Hom.: 50567 Cov.: 30

Gnomad AFR AF: 0.387

Gnomad AMI AF: 0.896

Gnomad AMR AF: 0.864

Gnomad ASJ AF: 0.886

Gnomad EAS AF: 0.892

Gnomad SAS AF: 0.848

Gnomad FIN AF: 0.954

Gnomad MID AF: 0.835

Gnomad NFE AF: 0.947

Gnomad OTH AF: 0.823

GnomAD3 exomes AF: 0.878 AC: 159748 AN: 181860 Hom.: 71852 AF XY: 0.886 AC XY: 85859 AN XY: 96856

Gnomad AFR exome AF: 0.376

Gnomad AMR exome AF: 0.869

Gnomad ASJ exome AF: 0.889

Gnomad EAS exome AF: 0.880

Gnomad SAS exome AF: 0.858

Gnomad FIN exome AF: 0.957

Gnomad NFE exome AF: 0.944

Gnomad OTH exome AF: 0.902

GnomAD4 exome AF: 0.924 AC: 1311334 AN: 1418846 Hom.: 612290 Cov.: 35 AF XY: 0.924 AC XY: 648215 AN XY: 701494

Gnomad4 AFR exome AF: 0.364

Gnomad4 AMR exome AF: 0.868

Gnomad4 ASJ exome AF: 0.888

Gnomad4 EAS exome AF: 0.898

Gnomad4 SAS exome AF: 0.861

Gnomad4 FIN exome AF: 0.951

Gnomad4 NFE exome AF: 0.951

Gnomad4 OTH exome AF: 0.892

GnomAD4 genome AF: 0.778 AC: 118328 AN: 152056 Hom.: 50582 Cov.: 30 AF XY: 0.783 AC XY: 58210 AN XY: 74348

Gnomad4 AFR AF: 0.387

Gnomad4 AMR AF: 0.864

Gnomad4 ASJ AF: 0.886

Gnomad4 EAS AF: 0.892

Gnomad4 SAS AF: 0.849

Gnomad4 FIN AF: 0.954

Gnomad4 NFE AF: 0.947

Gnomad4 OTH AF: 0.826

Alfa AF: 0.909 Hom.: 94527

Bravo AF: 0.753

TwinsUK AF: 0.950 AC: 3522

ALSPAC AF: 0.951 AC: 3664

ESP6500AA AF: 0.421 AC: 1839

ESP6500EA AF: 0.938 AC: 8019

ExAC AF: 0.847 AC: 95959

Asia WGS AF: 0.846 AC: 2943 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2019	- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Pathogenic	0.21
Cadd	Benign	6.3
Dann	Uncertain	0.98
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.38	T;T
MetaRNN	Benign	6.9e-7	T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P;P;P
PROVEAN	Benign	-0.81	N;N
REVEL	Uncertain	0.35
Sift	Benign	0.21	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.0	B;B
Vest4		0.19
ClinPred		0.0065	T
GERP RS		2.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs3780135; hg19: chr9-36840623; COSMIC: COSV63910740;