NM_016734.3:c.410+3705G>T

Variant names:

• chr9-37011292-C-A
• rs959396
• NM_016734.3:c.410+3705G>T

Variant summary

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

The NM_016734.3(PAX5):​c.410+3705G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.582 in 151,986 control chromosomes in the GnomAD database, including 25,992 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 0.58 (25992 hom., cov: 32)
• Consequence: PAX5 NM_016734.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.14
• Publications: 5 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.617 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX5	NM_016734.3	c.410+3705G>T		intron_variant	Intron 3 of 9	ENST00000358127.9	NP_057953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX5	ENST00000358127.9	c.410+3705G>T		intron_variant	Intron 3 of 9	1	NM_016734.3	ENSP00000350844.4

Frequencies

GnomAD3 genomes AF: 0.582 AC: 88326 AN: 151868 Hom.: 25972 Cov.: 32

Gnomad AFR AF: 0.561

Gnomad AMI AF: 0.704

Gnomad AMR AF: 0.538

Gnomad ASJ AF: 0.741

Gnomad EAS AF: 0.491

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.482

Gnomad MID AF: 0.801

Gnomad NFE AF: 0.622

Gnomad OTH AF: 0.644

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

GnomAD4 genome AF: 0.582 AC: 88396 AN: 151986 Hom.: 25992 Cov.: 32 AF XY: 0.573 AC XY: 42566 AN XY: 74298

African (AFR) AF: 0.561 AC: 23259 AN: 41430

American (AMR) AF: 0.539 AC: 8224 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.741 AC: 2571 AN: 3470

East Asian (EAS) AF: 0.492 AC: 2540 AN: 5162

South Asian (SAS) AF: 0.460 AC: 2211 AN: 4808

European-Finnish (FIN) AF: 0.482 AC: 5090 AN: 10562

Middle Eastern (MID) AF: 0.803 AC: 236 AN: 294

European-Non Finnish (NFE) AF: 0.622 AC: 42273 AN: 67968

Other (OTH) AF: 0.640 AC: 1350 AN: 2110

Alfa AF: 0.614 Hom.: 113231

Bravo AF: 0.589

Asia WGS AF: 0.463 AC: 1611 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	9.7
DANN	Benign	0.64
PhyloP100		1.1
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: rs959396; hg19: chr9-37011289; COSMIC: COSV63906169; COSMIC: COSV63906169;