9-36923440-G-C

Variant names:

• chr9-36923440-G-C
• rs143317078
• NM_016734.3:c.825C>G

Variant summary

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

The NM_016734.3(PAX5):​c.825C>G​(p.Asp275Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. D275N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAX5 NM_016734.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.274
• 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: 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX5	NM_016734.3	c.825C>G	p.Asp275Glu	missense_variant	Exon 7 of 10	ENST00000358127.9	NP_057953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX5	ENST00000358127.9	c.825C>G	p.Asp275Glu	missense_variant	Exon 7 of 10	1	NM_016734.3	ENSP00000350844.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	6.1
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T;.;.;.;.;T;T;.;.;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	1.1	L;L;L;.;.;.;.;.;L;.
PhyloP100		-0.27
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.2	N;N;N;N;N;N;D;N;N;D
REVEL	Uncertain	0.58
Sift	Benign	0.19	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.33	T;T;T;T;T;T;T;T;T;T
Polyphen		0.99	D;.;.;.;.;.;.;.;.;B
Vest4		0.49
MutPred		0.24		Gain of disorder (P = 0.2083);Gain of disorder (P = 0.2083);Gain of disorder (P = 0.2083);.;.;.;.;.;Gain of disorder (P = 0.2083);.;
MVP		0.98
MPC		0.51
ClinPred		0.77	D
GERP RS		-5.0
Varity_R		0.11
gMVP		0.45
Mutation Taster		=60/40	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: rs143317078; hg19: chr9-36923437;