rs528158465

Variant names:

• chr9-36840610-C-A
• rs528158465
• NM_016734.3:c.1126G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-36840610-C-A
• chr9-36840610-C-G
• chr9-36840610-C-T

Variant summary

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

The NM_016734.3(PAX5):​c.1126G>T​(p.Ala376Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,426,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. A376T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PAX5 NM_016734.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.27
• 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: 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=0.12380323).

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.1126G>T	p.Ala376Ser	missense	Exon 10 of 10	NP_057953.1	Q02548-1
	PAX5	NM_001280548.2		c.1039G>T	p.Ala347Ser	missense	Exon 9 of 9	NP_001267477.1	Q02548-2
	PAX5	NM_001280547.2		c.1024G>T	p.Ala342Ser	missense	Exon 9 of 9	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.1126G>T	p.Ala376Ser	missense	Exon 10 of 10	ENSP00000350844.4	Q02548-1
	PAX5	ENST00000377853.6	TSL:1	c.1039G>T	p.Ala347Ser	missense	Exon 9 of 9	ENSP00000367084.2	Q02548-2
	PAX5	ENST00000377852.7	TSL:1	c.1024G>T	p.Ala342Ser	missense	Exon 9 of 9	ENSP00000367083.2	Q02548-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1426720 Hom.: 0 Cov.: 30 AF XY: 0.00000142 AC XY: 1 AN XY: 706016

African (AFR) AF: 0.00 AC: 0 AN: 33256

American (AMR) AF: 0.00 AC: 0 AN: 38342

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25414

East Asian (EAS) AF: 0.0000260 AC: 1 AN: 38510

South Asian (SAS) AF: 0.00 AC: 0 AN: 81270

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095184

Other (OTH) AF: 0.00 AC: 0 AN: 59244

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	17
DANN	Benign	0.78
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	-0.84	N
PhyloP100		2.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.38	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0080	B
Vest4		0.23
MutPred		0.21		Gain of glycosylation at A376 (P = 7e-04)
MVP		0.69
MPC		0.44
ClinPred		0.13	T
GERP RS		5.1
Varity_R		0.059
gMVP		0.26
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs528158465; hg19: chr9-36840607;