1-164559874-G-T

Variant names:

• chr1-164559874-G-T
• rs544057798
• NM_002585.4:c.52G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001353130.1(PBX1):​c.-124G>T variant causes a 5 prime UTR premature start codon gain 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. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PBX1 NM_001353130.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.73
• Publications: 0 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.575
• PP5: Variant 1-164559874-G-T is Pathogenic according to our data. Variant chr1-164559874-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1098351.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353130.1. 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.52G>T	p.Gly18*	stop_gained	Exon 1 of 9	NP_002576.1	P40424-1
	PBX1	NM_001353130.1		c.-124G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_001340059.1
	PBX1	NM_001204963.2		c.52G>T	p.Gly18*	stop_gained	Exon 1 of 9	NP_001191892.1	P40424-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PBX1	ENST00000420696.7	TSL:1 MANE Select	c.52G>T	p.Gly18*	stop_gained	Exon 1 of 9	ENSP00000405890.2	P40424-1
	PBX1	ENST00000367897.5	TSL:1	c.52G>T	p.Gly18*	stop_gained	Exon 1 of 8	ENSP00000356872.1	P40424-2
	PBX1	ENST00000627490.2	TSL:2	c.52G>T	p.Gly18*	stop_gained	Exon 1 of 9	ENSP00000485692.1	P40424-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1398438 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 689698

African (AFR) AF: 0.00 AC: 0 AN: 31546

American (AMR) AF: 0.00 AC: 0 AN: 35664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25164

East Asian (EAS) AF: 0.00 AC: 0 AN: 35666

South Asian (SAS) AF: 0.00 AC: 0 AN: 79184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078766

Other (OTH) AF: 0.00 AC: 0 AN: 57930

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000248 AC: 2

ClinVar

ClinVar submissions

Significance: 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	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	45
DANN	Uncertain	0.99
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		7.7
Vest4		0.89
GERP RS		5.2
PromoterAI		-0.075	Neutral
Mutation Taster		=12/188	disease causing (fs/PTC)

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: rs544057798; hg19: chr1-164529111;