1-164799889-G-C

Variant names:

• chr1-164799889-G-C
• rs1553248112
• NM_002585.4:c.701G>C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_002585.4(PBX1):​c.701G>C​(p.Arg234Pro) 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. 14/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R234W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PBX1 NM_002585.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.46

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 11 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, 1 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 chr1-164799889-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559855.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: MetaRNN computational evidence supports a deleterious effect, 0.9
• PP5: Variant 1-164799889-G-C is Pathogenic according to our data. Variant chr1-164799889-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523089.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.701G>C	p.Arg234Pro	missense_variant, splice_region_variant	Exon 4 of 9	ENST00000420696.7	NP_002576.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PBX1	ENST00000420696.7	c.701G>C	p.Arg234Pro	missense_variant, splice_region_variant	Exon 4 of 9	1	NM_002585.4	ENSP00000405890.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

PBX1-related intellectual disability and pleiotropic developmental defects Pathogenic:1

Feb 28, 2019

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PBX1 c.701G>C (p.Arg234Pro) variant is a missense variant that has been reported in one study, in which it is found in a heterozygous state, presumed de novo, in 24 month old female proband (Slavotinek et al. 2017). The proband’s phenotype included global developmental delay, hypotonia and a history of a patent PDA ligation and pulmonary artery hypertension. Polyhydramnios and decreased fetal movements had led to emergency C-section at 32 weeks gestation. The p.Arg234Pro variant is not found in the Genome Aggregation Database. The Arg234 is a highly conserved residue located within the homeobox domain of PBX1. An in vitro luciferase assay, using heterologous expression of a PBX1 p.Arg234Pro construct, demonstrated that this variant has reduced transcriptional activity compared to the wild type (Slavotinek et al. 2017). Based on the collective evidence and application of the ACMG criteria, the PBX1 p.Arg234Pro variant is classified as likely pathogenic for PBX1-related intellectual disability and pleiotropic developmental defects. -

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	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.;.;D;.;T;T;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M;M;M;.;.;.;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.7	D;.;D;D;D;D;.;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0020	D;.;D;D;D;D;.;.
Sift4G	Uncertain	0.033	D;D;D;T;D;D;T;D
Polyphen		1.0	D;.;.;.;.;.;.;.
Vest4		0.77
MutPred		0.63		Loss of stability (P = 0.0643);Loss of stability (P = 0.0643);Loss of stability (P = 0.0643);Loss of stability (P = 0.0643);.;.;.;.;
MVP		0.95
MPC		3.6
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.96
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.040		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: rs1553248112; hg19: chr1-164769126;