rs34810717

Positions:

• chr9-36882052-C-T

Variant summary

Our verdict is Benign. Variant got -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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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:4 O:1
• Conservation: PhyloP100: 1.90

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 135003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-36882052-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1279 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX5	NM_016734.3	c.964G>A	p.Ala322Thr	missense_variant	8/10	ENST00000358127.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX5	ENST00000358127.9	c.964G>A	p.Ala322Thr	missense_variant	8/10	1	NM_016734.3	P1

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

GnomAD3 exomes AF: 0.00970 AC: 2356 AN: 242998 Hom.: 21 AF XY: 0.00977 AC XY: 1288 AN XY: 131828

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 SAS exome AF: 0.00606

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

Gnomad4 AFR exome AF: 0.00228

Gnomad4 AMR exome AF: 0.00788

Gnomad4 ASJ exome AF: 0.00745

Gnomad4 EAS exome AF: 0.000127

Gnomad4 SAS exome AF: 0.00582

Gnomad4 FIN exome AF: 0.00559

Gnomad4 NFE exome AF: 0.0154

Gnomad4 OTH exome AF: 0.0108

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

Gnomad4 AFR AF: 0.00313

Gnomad4 AMR AF: 0.00601

Gnomad4 ASJ AF: 0.00835

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00498

Gnomad4 FIN AF: 0.00386

Gnomad4 NFE AF: 0.0140

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.0128 Hom.: 30

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

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2021	This variant is associated with the following publications: (PMID: 24728327) -

not specified Benign:1 Other:1

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Computational scores

Source: dbNSFP v4.3

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;.;.;T;.;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T;T;T;T;T;T
MetaRNN	Benign	0.0043	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.3	N;N;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	1.9	N;N;N;N;N;N
REVEL	Benign	0.078
Sift	Benign	1.0	T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.047	B;.;.;.;.;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs34810717; hg19: chr9-36882049; COSMIC: COSV63906468;