rs1553249136

Variant names:

• chr1-164807544-G-A
• rs1553249136
• NM_002585.4:c.704G>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Moderate

The NM_002585.4(PBX1):​c.704G>A​(p.Arg235Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R235W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PBX1 NM_002585.4 missense, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.23

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_002585.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-164807543-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 829999.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the PBX1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 3.8266 (above the threshold of 3.09). Trascript score misZ: 4.2973 (above the threshold of 3.09). GenCC associations: The gene is linked to congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-164807544-G-A is Pathogenic according to our data. Variant chr1-164807544-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 523090.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PBX1	NM_002585.4	c.704G>A	p.Arg235Gln	missense_variant, splice_region_variant	Exon 5 of 9	ENST00000420696.7	NP_002576.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PBX1	ENST00000420696.7	c.704G>A	p.Arg235Gln	missense_variant, splice_region_variant	Exon 5 of 9	1	NM_002585.4	ENSP00000405890.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460496 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726472

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jan 06, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggested R235Q plays a dominant negative role and interacts with wild type PBX1 in target gene transactivation (Slavotinek et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In addition, in silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29036646, 28135719, 31058389, 31302614, 31785789) -

Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay Pathogenic:1

Apr 26, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	36
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;.;.;D;.;D;T;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.6	M;M;M;.;.;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.8	D;.;D;D;D;D;.;.
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;.;D;D;D;D;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.;.
Vest4		0.70
MutPred		0.59		Loss of methylation at K236 (P = 0.1719);Loss of methylation at K236 (P = 0.1719);Loss of methylation at K236 (P = 0.1719);Loss of methylation at K236 (P = 0.1719);.;.;.;.;
MVP		0.91
MPC		2.3
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.83
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.57		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.57		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553249136; hg19: chr1-164776781; COSMIC: COSV63344026;