9-36840599-G-C

Variant names:

• chr9-36840599-G-C
• rs139108915
• ENST00000523241.6:c.905C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001280549.2(PAX5):​c.905C>G​(p.Pro302Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,429,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P302L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PAX5 NM_001280549.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.69
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07193899).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001280549.2. 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.1137C>G	p.Ala379Ala	synonymous	Exon 10 of 10	NP_057953.1	Q02548-1
	PAX5	NM_001280549.2		c.905C>G	p.Pro302Arg	missense	Exon 8 of 8	NP_001267478.1	E7EQT0
	PAX5	NM_001280550.2		c.818C>G	p.Pro273Arg	missense	Exon 7 of 7	NP_001267479.1	E7ERW5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX5	ENST00000523241.6	TSL:1	c.905C>G	p.Pro302Arg	missense	Exon 8 of 8	ENSP00000429637.1	E7EQT0
	PAX5	ENST00000520154.6	TSL:1	c.818C>G	p.Pro273Arg	missense	Exon 7 of 7	ENSP00000429291.1	E7ERW5
	PAX5	ENST00000358127.9	TSL:1 MANE Select	c.1137C>G	p.Ala379Ala	synonymous	Exon 10 of 10	ENSP00000350844.4	Q02548-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1429648 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 707748

African (AFR) AF: 0.00 AC: 0 AN: 33286

American (AMR) AF: 0.00 AC: 0 AN: 38844

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25446

East Asian (EAS) AF: 0.00 AC: 0 AN: 38600

South Asian (SAS) AF: 0.00 AC: 0 AN: 81404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50134

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 9.12e-7 AC: 1 AN: 1096918

Other (OTH) AF: 0.00 AC: 0 AN: 59304

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	0.24
DANN	Benign	0.97
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.33	T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-0.46	T
PhyloP100		-3.7
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.35
Sift	Benign	0.24	T
Sift4G	Uncertain	0.0020	D
Polyphen		0.0	B
Vest4		0.15
MutPred		0.40		Loss of glycosylation at P302 (P = 0.0108)
MVP		0.60
ClinPred		0.092	T
GERP RS		-11
Mutation Taster		=81/19	polymorphism

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: rs139108915; hg19: chr9-36840596;