1-164799889-G-C

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong 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. 15/24 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 (★). ClinVar reports functional evidence for this variant: "SCV001451466: 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).". 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
• Publications: 1 publications found

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]

PBX1 Gene-Disease associations (from GenCC):

• congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Illumina, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001451466: 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).
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chr1-164799888-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1698904.
• 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 predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• 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 VariationId is 523089.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002585.4. 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
	PBX1	NM_002585.4	MANE Select	c.701G>C	p.Arg234Pro	missense splice_region	Exon 4 of 9	NP_002576.1	P40424-1
	PBX1	NM_001204963.2		c.701G>C	p.Arg234Pro	missense splice_region	Exon 4 of 9	NP_001191892.1	P40424-3
	PBX1	NM_001204961.2		c.701G>C	p.Arg234Pro	missense splice_region	Exon 4 of 8	NP_001191890.1	Q53YC7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PBX1	ENST00000420696.7	TSL:1 MANE Select	c.701G>C	p.Arg234Pro	missense splice_region	Exon 4 of 9	ENSP00000405890.2	P40424-1
	PBX1	ENST00000367897.5	TSL:1	c.701G>C	p.Arg234Pro	missense splice_region	Exon 4 of 8	ENSP00000356872.1	P40424-2
	PBX1	ENST00000540236.4	TSL:1	c.386G>C	p.Arg129Pro	missense splice_region	Exon 2 of 7	ENSP00000439943.3	H0YLB0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (1)
1	-	-	PBX1-related intellectual disability and pleiotropic developmental defects (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		9.5
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.033	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.63		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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1553248112; hg19: chr1-164769126;