1-164850925-A-G

Variant names:

• chr1-164850925-A-G
• rs12723035
• NM_002585.4:c.*4249A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002585.4(PBX1):​c.*4249A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.362 in 211,450 control chromosomes in the GnomAD database, including 14,680 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.37 (11103 hom., cov: 32)
  • Exomes 𝑓: 0.34 (3577 hom.)
• Consequence: PBX1 NM_002585.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.498
• Publications: 6 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Illumina, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.486 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PBX1	NM_002585.4	MANE Select	c.*4249A>G		3_prime_UTR	Exon 9 of 9	NP_002576.1
	PBX1	NM_001204963.2		c.*1523A>G		3_prime_UTR	Exon 9 of 9	NP_001191892.1
	PBX1	NM_001204961.2		c.*4385A>G		3_prime_UTR	Exon 8 of 8	NP_001191890.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PBX1	ENST00000420696.7	TSL:1 MANE Select	c.*4249A>G		3_prime_UTR	Exon 9 of 9	ENSP00000405890.2
	PBX1	ENST00000699845.1		c.*43+29299A>G		intron	N/A	ENSP00000514643.1
	PBX1	ENST00000699848.1		c.756+29299A>G		intron	N/A	ENSP00000514646.1

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56365 AN: 151870 Hom.: 11073 Cov.: 32

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.284

Gnomad ASJ AF: 0.440

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.375

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.327

Gnomad OTH AF: 0.379

GnomAD4 exome AF: 0.337 AC: 20009 AN: 59462 Hom.: 3577 Cov.: 0 AF XY: 0.340 AC XY: 9343 AN XY: 27478

African (AFR) AF: 0.497 AC: 1337 AN: 2692

American (AMR) AF: 0.248 AC: 439 AN: 1772

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 1608 AN: 3774

East Asian (EAS) AF: 0.218 AC: 1969 AN: 9026

South Asian (SAS) AF: 0.382 AC: 191 AN: 500

European-Finnish (FIN) AF: 0.333 AC: 16 AN: 48

Middle Eastern (MID) AF: 0.380 AC: 140 AN: 368

European-Non Finnish (NFE) AF: 0.344 AC: 12505 AN: 36318

Other (OTH) AF: 0.363 AC: 1804 AN: 4964

GnomAD4 genome AF: 0.371 AC: 56447 AN: 151988 Hom.: 11103 Cov.: 32 AF XY: 0.371 AC XY: 27551 AN XY: 74288

African (AFR) AF: 0.491 AC: 20342 AN: 41404

American (AMR) AF: 0.284 AC: 4333 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.440 AC: 1526 AN: 3468

East Asian (EAS) AF: 0.220 AC: 1134 AN: 5154

South Asian (SAS) AF: 0.376 AC: 1815 AN: 4822

European-Finnish (FIN) AF: 0.351 AC: 3705 AN: 10570

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.327 AC: 22246 AN: 67992

Other (OTH) AF: 0.383 AC: 805 AN: 2102

Alfa AF: 0.360 Hom.: 4228

Bravo AF: 0.367

Asia WGS AF: 0.336 AC: 1166 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.36
DANN	Benign	0.36
PhyloP100		-0.50
Mutation Taster		=100/0	polymorphism (auto)

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: rs12723035; hg19: chr1-164820162;