9-37034026-A-T

Variant names:

• chr9-37034026-A-T
• rs139701864
• NM_016734.3:c.6T>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.6T>A​(p.Asp2Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,605,240 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (17 hom.)
• Consequence: PAX5 NM_016734.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 2.38
• Publications: 7 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]

EBLN3P (HGNC:50682): (endogenous Bornavirus like nucleoprotein 3, pseudogene)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008341283).
• BP6: Variant 9-37034026-A-T is Benign according to our data. Variant chr9-37034026-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00236 (351/148970) while in subpopulation EAS AF = 0.0107 (54/5034). AF 95% confidence interval is 0.00844. There are 7 homozygotes in GnomAd4. There are 227 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX5	NM_016734.3	MANE Select	c.6T>A	p.Asp2Glu	missense	Exon 1 of 10	NP_057953.1
	PAX5	NM_001280548.2		c.6T>A	p.Asp2Glu	missense	Exon 1 of 9	NP_001267477.1
	PAX5	NM_001280547.2		c.6T>A	p.Asp2Glu	missense	Exon 1 of 9	NP_001267476.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX5	ENST00000358127.9	TSL:1 MANE Select	c.6T>A	p.Asp2Glu	missense	Exon 1 of 10	ENSP00000350844.4
	PAX5	ENST00000377853.6	TSL:1	c.6T>A	p.Asp2Glu	missense	Exon 1 of 9	ENSP00000367084.2
	PAX5	ENST00000377852.7	TSL:1	c.6T>A	p.Asp2Glu	missense	Exon 1 of 9	ENSP00000367083.2

Frequencies

GnomAD3 genomes AF: 0.00236 AC: 352 AN: 148914 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.000200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0107

Gnomad SAS AF: 0.000429

Gnomad FIN AF: 0.0263

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000428

Gnomad OTH AF: 0.00196

GnomAD2 exomes AF: 0.00327 AC: 809 AN: 247530 AF XY: 0.00313

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0107

Gnomad FIN exome AF: 0.0223

Gnomad NFE exome AF: 0.000949

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.00134 AC: 1949 AN: 1456270 Hom.: 17 Cov.: 30 AF XY: 0.00128 AC XY: 931 AN XY: 724594

African (AFR) AF: 0.0000900 AC: 3 AN: 33316

American (AMR) AF: 0.0000224 AC: 1 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00710 AC: 280 AN: 39446

South Asian (SAS) AF: 0.000280 AC: 24 AN: 85838

European-Finnish (FIN) AF: 0.0225 AC: 1201 AN: 53336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4384

European-Non Finnish (NFE) AF: 0.000260 AC: 288 AN: 1109098

Other (OTH) AF: 0.00253 AC: 152 AN: 60082

GnomAD4 genome AF: 0.00236 AC: 351 AN: 148970 Hom.: 7 Cov.: 31 AF XY: 0.00313 AC XY: 227 AN XY: 72478

African (AFR) AF: 0.000199 AC: 8 AN: 40144

American (AMR) AF: 0.00 AC: 0 AN: 15002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.0107 AC: 54 AN: 5034

South Asian (SAS) AF: 0.000430 AC: 2 AN: 4652

European-Finnish (FIN) AF: 0.0263 AC: 255 AN: 9692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.000428 AC: 29 AN: 67746

Other (OTH) AF: 0.00146 AC: 3 AN: 2050

Alfa AF: 0.000829 Hom.: 0

Bravo AF: 0.000570

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00295 AC: 358

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0083	T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	0.46	N
PhyloP100		2.4
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.26
Sift	Benign	0.23	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.25
MutPred		0.14		Gain of loop (P = 0.1081)
MVP		0.88
MPC		1.3
ClinPred		0.022	T
GERP RS		4.9
PromoterAI		-0.026	Neutral
Varity_R		0.087
gMVP		0.56
Mutation Taster		=289/11	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: rs139701864; hg19: chr9-37034023;