1-164559874-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_002585.4(PBX1):​c.52G>C​(p.Gly18Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,440 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: PBX1 NM_002585.4 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

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.52G>C	p.Gly18Arg	missense	Exon 1 of 9	NP_002576.1	P40424-1
	PBX1	NM_001204963.2		c.52G>C	p.Gly18Arg	missense	Exon 1 of 9	NP_001191892.1	P40424-3
	PBX1	NM_001204961.2		c.52G>C	p.Gly18Arg	missense	Exon 1 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.52G>C	p.Gly18Arg	missense	Exon 1 of 9	ENSP00000405890.2	P40424-1
	PBX1	ENST00000367897.5	TSL:1	c.52G>C	p.Gly18Arg	missense	Exon 1 of 8	ENSP00000356872.1	P40424-2
	PBX1	ENST00000627490.2	TSL:2	c.52G>C	p.Gly18Arg	missense	Exon 1 of 9	ENSP00000485692.1	P40424-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00 AC: 0 AN: 154462 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398440 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 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: 5314

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078766

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

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	2.0	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.58
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.024	D
Polyphen		0.98	D
Vest4		0.82
MutPred		0.31		Gain of MoRF binding (P = 0.0172)
MVP		0.90
MPC		0.16
ClinPred		0.98	D
GERP RS		5.2
PromoterAI		-0.0020	Neutral
Varity_R		0.32
gMVP		0.48
Mutation Taster		=56/44	polymorphism

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;