rs137870876

Variant names:

• chr9-36966691-G-A
• rs137870876
• NM_016734.3:c.638C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-36966691-G-A
• chr9-36966691-G-T
• chr9-36966691-G-C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_016734.3(PAX5):​c.638C>T​(p.Ser213Leu) variant causes a missense change. The variant allele was found at a frequency of 0.001 in 1,614,082 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S213S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (2 hom.)
• Consequence: PAX5 NM_016734.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2 O:1
• Conservation: PhyloP100: 5.66
• Publications: 13 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25095463).
• BP6: Variant 9-36966691-G-A is Benign according to our data. Variant chr9-36966691-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135001.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000604 (92/152226) while in subpopulation NFE AF = 0.00115 (78/68032). AF 95% confidence interval is 0.000941. There are 0 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.638C>T	p.Ser213Leu	missense	Exon 6 of 10	NP_057953.1	Q02548-1
	PAX5	NM_001280548.2		c.638C>T	p.Ser213Leu	missense	Exon 6 of 9	NP_001267477.1	Q02548-2
	PAX5	NM_001280547.2		c.638C>T	p.Ser213Leu	missense	Exon 6 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.638C>T	p.Ser213Leu	missense	Exon 6 of 10	ENSP00000350844.4	Q02548-1
	PAX5	ENST00000377853.6	TSL:1	c.638C>T	p.Ser213Leu	missense	Exon 6 of 9	ENSP00000367084.2	Q02548-2
	PAX5	ENST00000377852.7	TSL:1	c.638C>T	p.Ser213Leu	missense	Exon 6 of 9	ENSP00000367083.2	Q02548-6

Frequencies

GnomAD3 genomes AF: 0.000604 AC: 92 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000621 AC: 156 AN: 251306 AF XY: 0.000545

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.00104 AC: 1525 AN: 1461856 Hom.: 2 Cov.: 31 AF XY: 0.00100 AC XY: 729 AN XY: 727230

African (AFR) AF: 0.000209 AC: 7 AN: 33478

American (AMR) AF: 0.000268 AC: 12 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000336 AC: 29 AN: 86258

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53410

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00128 AC: 1421 AN: 1111992

Other (OTH) AF: 0.000828 AC: 50 AN: 60396

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.000444 AC XY: 33 AN XY: 74366

African (AFR) AF: 0.000145 AC: 6 AN: 41456

American (AMR) AF: 0.000131 AC: 2 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00115 AC: 78 AN: 68032

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000858 Hom.: 0

Bravo AF: 0.000638

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000659 AC: 80

EpiCase AF: 0.00136

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	1	not provided (5)
-	-	1	Leukemia, acute lymphoblastic, susceptibility to, 3 (1)
-	1	-	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.25	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.7
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.049	D
Polyphen		0.46	P
Vest4		0.42
MVP		0.91
MPC		0.91
ClinPred		0.079	T
GERP RS		5.5
Varity_R		0.29
gMVP		0.59
Mutation Taster		=30/70	disease causing

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: rs137870876; hg19: chr9-36966688; COSMIC: COSV99050257; COSMIC: COSV99050257;