1-164559883-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_002585.4(PBX1):c.61G>A(p.Gly21Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,550,066 control chromosomes in the GnomAD database, including 51,948 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (4494 hom., cov: 31)
  • Exomes 𝑓: 0.24 (47454 hom.)
• Consequence: PBX1 NM_002585.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 8.01

Genes affected

PBX1 (HGNC:8632): (PBX homeobox 1) This gene encodes a nuclear protein that belongs to the PBX homeobox family of transcriptional factors. Studies in mice suggest that this gene may be involved in the regulation of osteogenesis and required for skeletal patterning and programming. A chromosomal translocation, t(1;19) involving this gene and TCF3/E2A gene, is associated with pre-B-cell acute lymphoblastic leukemia. The resulting fusion protein, in which the DNA binding domain of E2A is replaced by the DNA binding domain of this protein, transforms cells by constitutively activating transcription of genes regulated by the PBX protein family. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2017]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PBX1
• BP4: Computational evidence support a benign effect (MetaRNN=2.8911233E-4).
• BP6: Variant 1-164559883-G-A is Benign according to our data. Variant chr1-164559883-G-A is described in ClinVar as [Benign]. Clinvar id is 1288942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PBX1	NM_002585.4	c.61G>A	p.Gly21Ser	missense_variant	1/9	ENST00000420696.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PBX1	ENST00000420696.7	c.61G>A	p.Gly21Ser	missense_variant	1/9	1	NM_002585.4	P4

Frequencies

GnomAD3 genomes AF: 0.204 AC: 30976 AN: 151828 Hom.: 4492 Cov.: 31

Gnomad AFR AF: 0.0447

Gnomad AMI AF: 0.278

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.631

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.211

GnomAD3 exomes AF: 0.304 AC: 46889 AN: 154030 Hom.: 9052 AF XY: 0.304 AC XY: 24813 AN XY: 81636

Gnomad AFR exome AF: 0.0372

Gnomad AMR exome AF: 0.477

Gnomad ASJ exome AF: 0.245

Gnomad EAS exome AF: 0.632

Gnomad SAS exome AF: 0.378

Gnomad FIN exome AF: 0.208

Gnomad NFE exome AF: 0.217

Gnomad OTH exome AF: 0.256

GnomAD4 exome AF: 0.241 AC: 336771 AN: 1398128 Hom.: 47454 Cov.: 37 AF XY: 0.245 AC XY: 168880 AN XY: 689538

Gnomad4 AFR exome AF: 0.0357

Gnomad4 AMR exome AF: 0.466

Gnomad4 ASJ exome AF: 0.243

Gnomad4 EAS exome AF: 0.679

Gnomad4 SAS exome AF: 0.376

Gnomad4 FIN exome AF: 0.207

Gnomad4 NFE exome AF: 0.217

Gnomad4 OTH exome AF: 0.244

GnomAD4 genome AF: 0.204 AC: 30981 AN: 151938 Hom.: 4494 Cov.: 31 AF XY: 0.213 AC XY: 15845 AN XY: 74236

Gnomad4 AFR AF: 0.0446

Gnomad4 AMR AF: 0.360

Gnomad4 ASJ AF: 0.234

Gnomad4 EAS AF: 0.632

Gnomad4 SAS AF: 0.378

Gnomad4 FIN AF: 0.212

Gnomad4 NFE AF: 0.218

Gnomad4 OTH AF: 0.211

Alfa AF: 0.226 Hom.: 6216

Bravo AF: 0.209

TwinsUK AF: 0.218 AC: 808

ALSPAC AF: 0.214 AC: 825

ESP6500AA AF: 0.0408 AC: 168

ESP6500EA AF: 0.188 AC: 1503

ExAC AF: 0.171 AC: 12421

Asia WGS AF: 0.448 AC: 1555 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2020	This variant is associated with the following publications: (PMID: 31934099) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.20
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.28	T;T;T;.;.;T
Eigen	Benign	-0.011
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	T;T;T;T;T;T
MetaRNN	Benign	0.00029	T;T;T;T;T;T
MetaSVM	Benign	-0.50	T
MutationTaster	Benign	5.0e-7	P;P;P;P;P
PrimateAI	Pathogenic	0.87	D
Sift4G	Benign	0.083	T;T;T;T;T;T
Polyphen		0.49	.;.;P;.;.;.
Vest4		0.43
MPC		0.050
ClinPred		0.043	T
GERP RS		5.2
Varity_R		0.12
gMVP		0.46

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: rs2275558; hg19: chr1-164529120; COSMIC: COSV61532892; COSMIC: COSV61532892;