rs3739437

Variant names:

• chr9-36840449-G-A
• rs3739437
• NM_016734.3:c.*111C>T

Variant summary

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

The NM_016734.3(PAX5):​c.*111C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0288 in 1,050,558 control chromosomes in the GnomAD database, including 1,106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (100 hom., cov: 32)
  • Exomes 𝑓: 0.030 (1006 hom.)
• Consequence: PAX5 NM_016734.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.308
• Publications: 2 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 (BayesDel_noAF=-0.88).
• BP6: Variant 9-36840449-G-A is Benign according to our data. Variant chr9-36840449-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1254811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

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.*111C>T		3_prime_UTR	Exon 10 of 10	NP_057953.1	Q02548-1
	PAX5	NM_001280548.2		c.*111C>T		3_prime_UTR	Exon 9 of 9	NP_001267477.1	Q02548-2
	PAX5	NM_001280547.2		c.*111C>T		3_prime_UTR	Exon 9 of 9	NP_001267476.1	Q02548-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX5	ENST00000358127.9	TSL:1 MANE Select	c.*111C>T		3_prime_UTR	Exon 10 of 10	ENSP00000350844.4	Q02548-1
	PAX5	ENST00000377853.6	TSL:1	c.*111C>T		3_prime_UTR	Exon 9 of 9	ENSP00000367084.2	Q02548-2
	PAX5	ENST00000377852.7	TSL:1	c.*111C>T		3_prime_UTR	Exon 9 of 9	ENSP00000367083.2	Q02548-6

Frequencies

GnomAD3 genomes AF: 0.0239 AC: 3637 AN: 152158 Hom.: 100 Cov.: 32

Gnomad AFR AF: 0.00842

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0443

Gnomad ASJ AF: 0.0499

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0243

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0143

Gnomad OTH AF: 0.0335

GnomAD4 exome AF: 0.0296 AC: 26605 AN: 898282 Hom.: 1006 Cov.: 12 AF XY: 0.0330 AC XY: 15248 AN XY: 462480

African (AFR) AF: 0.00945 AC: 217 AN: 22966

American (AMR) AF: 0.0775 AC: 2713 AN: 35018

Ashkenazi Jewish (ASJ) AF: 0.0505 AC: 1117 AN: 22114

East Asian (EAS) AF: 0.0999 AC: 3350 AN: 33534

South Asian (SAS) AF: 0.114 AC: 7899 AN: 69564

European-Finnish (FIN) AF: 0.0245 AC: 898 AN: 36664

Middle Eastern (MID) AF: 0.0517 AC: 171 AN: 3310

European-Non Finnish (NFE) AF: 0.0139 AC: 8786 AN: 633200

Other (OTH) AF: 0.0347 AC: 1454 AN: 41912

GnomAD4 genome AF: 0.0239 AC: 3635 AN: 152276 Hom.: 100 Cov.: 32 AF XY: 0.0267 AC XY: 1989 AN XY: 74456

African (AFR) AF: 0.00844 AC: 351 AN: 41570

American (AMR) AF: 0.0443 AC: 677 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0499 AC: 173 AN: 3468

East Asian (EAS) AF: 0.107 AC: 555 AN: 5170

South Asian (SAS) AF: 0.118 AC: 569 AN: 4814

European-Finnish (FIN) AF: 0.0243 AC: 258 AN: 10608

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0143 AC: 972 AN: 68036

Other (OTH) AF: 0.0322 AC: 68 AN: 2112

Alfa AF: 0.0208 Hom.: 73

Bravo AF: 0.0264

Asia WGS AF: 0.0950 AC: 329 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.9
DANN	Benign	0.78
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism (auto)

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: rs3739437; hg19: chr9-36840446; COSMIC: COSV63905038; COSMIC: COSV63905038;