rs3780135

Variant names:

• chr9-36840626-G-A
• rs3780135
• ENST00000523241.6:c.878C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-36840626-G-A
• chr9-36840626-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001280549.2(PAX5):​c.878C>T​(p.Thr293Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.91 in 1,570,902 control chromosomes in the GnomAD database, including 662,872 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T293V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.78 (50582 hom., cov: 30)
  • Exomes 𝑓: 0.92 (612290 hom.)
• Consequence: PAX5 NM_001280549.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 0.626
• Publications: 33 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.8845094E-7).
• BP6: Variant 9-36840626-G-A is Benign according to our data. Variant chr9-36840626-G-A is described in ClinVar as Benign. ClinVar VariationId is 134998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.941 is higher than 0.05.

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.1110C>T	p.Tyr370Tyr	synonymous	Exon 10 of 10	NP_057953.1	Q02548-1
	PAX5	NM_001280549.2		c.878C>T	p.Thr293Ile	missense	Exon 8 of 8	NP_001267478.1	E7EQT0
	PAX5	NM_001280550.2		c.791C>T	p.Thr264Ile	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.878C>T	p.Thr293Ile	missense	Exon 8 of 8	ENSP00000429637.1	E7EQT0
	PAX5	ENST00000520154.6	TSL:1	c.791C>T	p.Thr264Ile	missense	Exon 7 of 7	ENSP00000429291.1	E7ERW5
	PAX5	ENST00000358127.9	TSL:1 MANE Select	c.1110C>T	p.Tyr370Tyr	synonymous	Exon 10 of 10	ENSP00000350844.4	Q02548-1

Frequencies

GnomAD3 genomes AF: 0.778 AC: 118283 AN: 151938 Hom.: 50567 Cov.: 30

Gnomad AFR AF: 0.387

Gnomad AMI AF: 0.896

Gnomad AMR AF: 0.864

Gnomad ASJ AF: 0.886

Gnomad EAS AF: 0.892

Gnomad SAS AF: 0.848

Gnomad FIN AF: 0.954

Gnomad MID AF: 0.835

Gnomad NFE AF: 0.947

Gnomad OTH AF: 0.823

GnomAD2 exomes AF: 0.878 AC: 159748 AN: 181860 AF XY: 0.886

Gnomad AFR exome AF: 0.376

Gnomad AMR exome AF: 0.869

Gnomad ASJ exome AF: 0.889

Gnomad EAS exome AF: 0.880

Gnomad FIN exome AF: 0.957

Gnomad NFE exome AF: 0.944

Gnomad OTH exome AF: 0.902

GnomAD4 exome AF: 0.924 AC: 1311334 AN: 1418846 Hom.: 612290 Cov.: 35 AF XY: 0.924 AC XY: 648215 AN XY: 701494

African (AFR) AF: 0.364 AC: 12035 AN: 33072

American (AMR) AF: 0.868 AC: 32490 AN: 37418

Ashkenazi Jewish (ASJ) AF: 0.888 AC: 22476 AN: 25316

East Asian (EAS) AF: 0.898 AC: 34343 AN: 38248

South Asian (SAS) AF: 0.861 AC: 69450 AN: 80650

European-Finnish (FIN) AF: 0.951 AC: 46669 AN: 49062

Middle Eastern (MID) AF: 0.847 AC: 4837 AN: 5710

European-Non Finnish (NFE) AF: 0.951 AC: 1036490 AN: 1090456

Other (OTH) AF: 0.892 AC: 52544 AN: 58914

GnomAD4 genome AF: 0.778 AC: 118328 AN: 152056 Hom.: 50582 Cov.: 30 AF XY: 0.783 AC XY: 58210 AN XY: 74348

African (AFR) AF: 0.387 AC: 16033 AN: 41418

American (AMR) AF: 0.864 AC: 13206 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.886 AC: 3076 AN: 3470

East Asian (EAS) AF: 0.892 AC: 4612 AN: 5170

South Asian (SAS) AF: 0.849 AC: 4080 AN: 4806

European-Finnish (FIN) AF: 0.954 AC: 10121 AN: 10608

Middle Eastern (MID) AF: 0.837 AC: 246 AN: 294

European-Non Finnish (NFE) AF: 0.947 AC: 64396 AN: 67984

Other (OTH) AF: 0.826 AC: 1741 AN: 2108

Alfa AF: 0.882 Hom.: 132203

Bravo AF: 0.753

TwinsUK AF: 0.950 AC: 3522

ALSPAC AF: 0.951 AC: 3664

ESP6500AA AF: 0.421 AC: 1839

ESP6500EA AF: 0.938 AC: 8019

ExAC AF: 0.847 AC: 95959

Asia WGS AF: 0.846 AC: 2943 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	6.3
DANN	Uncertain	0.98
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.38	T
MetaRNN	Benign	6.9e-7	T
MetaSVM	Benign	-0.92	T
PhyloP100		0.63
PROVEAN	Benign	-0.81	N
REVEL	Uncertain	0.35
Sift	Benign	0.21	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.19
ClinPred		0.0065	T
GERP RS		2.4
Mutation Taster		=85/15	polymorphism (auto)

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: rs3780135; hg19: chr9-36840623; COSMIC: COSV63910740;