rs34810717

Variant names:

• chr9-36882052-C-T
• rs34810717
• NM_016734.3:c.964G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-36882052-C-T
• chr9-36882052-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016734.3(PAX5):​c.964G>A​(p.Ala322Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,611,354 control chromosomes in the GnomAD database, including 160 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (9 hom., cov: 31)
  • Exomes 𝑓: 0.013 (151 hom.)
• Consequence: PAX5 NM_016734.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 1.90
• Publications: 10 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=0.0043126345).
• BP6: Variant 9-36882052-C-T is Benign according to our data. Variant chr9-36882052-C-T is described in ClinVar as Benign. ClinVar VariationId is 135003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0084 (1279/152186) while in subpopulation NFE AF = 0.014 (950/67972). AF 95% confidence interval is 0.0132. There are 9 homozygotes in GnomAd4. There are 582 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR gene

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.964G>A	p.Ala322Thr	missense	Exon 8 of 10	NP_057953.1	Q02548-1
	PAX5	NM_001280548.2		c.964G>A	p.Ala322Thr	missense	Exon 8 of 9	NP_001267477.1	Q02548-2
	PAX5	NM_001280554.2		c.835G>A	p.Ala279Thr	missense	Exon 7 of 9	NP_001267483.1	Q02548-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX5	ENST00000358127.9	TSL:1 MANE Select	c.964G>A	p.Ala322Thr	missense	Exon 8 of 10	ENSP00000350844.4	Q02548-1
	PAX5	ENST00000377853.6	TSL:1	c.964G>A	p.Ala322Thr	missense	Exon 8 of 9	ENSP00000367084.2	Q02548-2
	PAX5	ENST00000414447.5	TSL:1	c.835G>A	p.Ala279Thr	missense	Exon 7 of 9	ENSP00000412188.1	Q02548-8

Frequencies

GnomAD3 genomes AF: 0.00841 AC: 1279 AN: 152068 Hom.: 9 Cov.: 31

Gnomad AFR AF: 0.00314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00498

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00970 AC: 2356 AN: 242998 AF XY: 0.00977

Gnomad AFR exome AF: 0.00309

Gnomad AMR exome AF: 0.00766

Gnomad ASJ exome AF: 0.00746

Gnomad EAS exome AF: 0.000168

Gnomad FIN exome AF: 0.00575

Gnomad NFE exome AF: 0.0144

Gnomad OTH exome AF: 0.0152

GnomAD4 exome AF: 0.0132 AC: 19192 AN: 1459168 Hom.: 151 Cov.: 31 AF XY: 0.0129 AC XY: 9373 AN XY: 725630

African (AFR) AF: 0.00228 AC: 76 AN: 33370

American (AMR) AF: 0.00788 AC: 351 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.00745 AC: 194 AN: 26038

East Asian (EAS) AF: 0.000127 AC: 5 AN: 39518

South Asian (SAS) AF: 0.00582 AC: 501 AN: 86040

European-Finnish (FIN) AF: 0.00559 AC: 298 AN: 53312

Middle Eastern (MID) AF: 0.00209 AC: 12 AN: 5748

European-Non Finnish (NFE) AF: 0.0154 AC: 17103 AN: 1110356

Other (OTH) AF: 0.0108 AC: 652 AN: 60248

GnomAD4 genome AF: 0.00840 AC: 1279 AN: 152186 Hom.: 9 Cov.: 31 AF XY: 0.00782 AC XY: 582 AN XY: 74402

African (AFR) AF: 0.00313 AC: 130 AN: 41528

American (AMR) AF: 0.00601 AC: 92 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00835 AC: 29 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00498 AC: 24 AN: 4818

European-Finnish (FIN) AF: 0.00386 AC: 41 AN: 10612

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0140 AC: 950 AN: 67972

Other (OTH) AF: 0.00569 AC: 12 AN: 2108

Alfa AF: 0.0123 Hom.: 32

Bravo AF: 0.00870

TwinsUK AF: 0.0148 AC: 55

ALSPAC AF: 0.0208 AC: 80

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0150 AC: 129

ExAC AF: 0.00982 AC: 1192

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.3	N
PhyloP100		1.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	1.9	N
REVEL	Benign	0.078
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.047	B
Vest4		0.36
MVP		0.25
MPC		0.47
ClinPred		0.016	T
GERP RS		5.1
Varity_R		0.10
gMVP		0.36
Mutation Taster		=76/24	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: rs34810717; hg19: chr9-36882049;