NM_016734.3:c.911-12049G>A

Variant names:

• chr9-36894154-C-T
• rs11999298
• NM_016734.3:c.911-12049G>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.911-12049G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0594 in 152,214 control chromosomes in the GnomAD database, including 316 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 0.059 (316 hom., cov: 32)
• Consequence: PAX5 NM_016734.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.474
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 (EAS) allele frequency at 95% confidence interval = 0.09 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016734.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX5	NM_016734.3	MANE Select	c.911-12049G>A		intron	N/A	NP_057953.1	Q02548-1
	PAX5	NM_001280548.2		c.911-12049G>A		intron	N/A	NP_001267477.1	Q02548-2
	PAX5	NM_001280547.2		c.910+29201G>A		intron	N/A	NP_001267476.1	Q02548-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX5	ENST00000358127.9	TSL:1 MANE Select	c.911-12049G>A		intron	N/A	ENSP00000350844.4	Q02548-1
	PAX5	ENST00000377853.6	TSL:1	c.911-12049G>A		intron	N/A	ENSP00000367084.2	Q02548-2
	PAX5	ENST00000377852.7	TSL:1	c.910+29201G>A		intron	N/A	ENSP00000367083.2	Q02548-6

Frequencies

GnomAD3 genomes AF: 0.0593 AC: 9024 AN: 152096 Hom.: 313 Cov.: 32

Gnomad AFR AF: 0.0805

Gnomad AMI AF: 0.0516

Gnomad AMR AF: 0.0533

Gnomad ASJ AF: 0.0701

Gnomad EAS AF: 0.0962

Gnomad SAS AF: 0.0603

Gnomad FIN AF: 0.0264

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0494

Gnomad OTH AF: 0.0602

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

GnomAD4 genome AF: 0.0594 AC: 9040 AN: 152214 Hom.: 316 Cov.: 32 AF XY: 0.0589 AC XY: 4386 AN XY: 74430

African (AFR) AF: 0.0806 AC: 3347 AN: 41522

American (AMR) AF: 0.0531 AC: 813 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0701 AC: 243 AN: 3468

East Asian (EAS) AF: 0.0970 AC: 501 AN: 5164

South Asian (SAS) AF: 0.0612 AC: 295 AN: 4820

European-Finnish (FIN) AF: 0.0264 AC: 280 AN: 10610

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0494 AC: 3360 AN: 68012

Other (OTH) AF: 0.0591 AC: 125 AN: 2114

Alfa AF: 0.0501 Hom.: 357

Bravo AF: 0.0637

Asia WGS AF: 0.0680 AC: 235 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	10
DANN	Benign	0.90
PhyloP100		-0.47
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: rs11999298; hg19: chr9-36894151;