9-36969208-G-T

Variant names:

• chr9-36969208-G-T
• rs16933812
• NM_016734.3:c.605-2484C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016734.3(PAX5):​c.605-2484C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.563 in 152,094 control chromosomes in the GnomAD database, including 25,998 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.56 (25998 hom., cov: 33)
• Consequence: PAX5 NM_016734.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.03
• Publications: 25 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.757 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX5	NM_016734.3	c.605-2484C>A		intron_variant	Intron 5 of 9	ENST00000358127.9	NP_057953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX5	ENST00000358127.9	c.605-2484C>A		intron_variant	Intron 5 of 9	1	NM_016734.3	ENSP00000350844.4

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85653 AN: 151976 Hom.: 25996 Cov.: 33

Gnomad AFR AF: 0.320

Gnomad AMI AF: 0.576

Gnomad AMR AF: 0.635

Gnomad ASJ AF: 0.566

Gnomad EAS AF: 0.777

Gnomad SAS AF: 0.703

Gnomad FIN AF: 0.637

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.562

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.563 AC: 85684 AN: 152094 Hom.: 25998 Cov.: 33 AF XY: 0.567 AC XY: 42140 AN XY: 74362

African (AFR) AF: 0.320 AC: 13272 AN: 41480

American (AMR) AF: 0.635 AC: 9716 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.566 AC: 1963 AN: 3468

East Asian (EAS) AF: 0.777 AC: 4001 AN: 5150

South Asian (SAS) AF: 0.703 AC: 3388 AN: 4816

European-Finnish (FIN) AF: 0.637 AC: 6742 AN: 10592

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.658 AC: 44708 AN: 67976

Other (OTH) AF: 0.565 AC: 1189 AN: 2106

Alfa AF: 0.702 Hom.: 40992

Bravo AF: 0.550

Asia WGS AF: 0.730 AC: 2537 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.090
DANN	Benign	0.50
PhyloP100		-2.0
Mutation Taster		=100/0	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: rs16933812; hg19: chr9-36969205;