1-164563088-T-C

Variant names:

• chr1-164563088-T-C
• rs4657364
• NM_002585.4:c.192-150T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_002585.4(PBX1):​c.192-150T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 505,780 control chromosomes in the GnomAD database, including 17,514 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 0.29 (8387 hom., cov: 32)
  • Exomes 𝑓: 0.20 (9127 hom.)
• Consequence: PBX1 NM_002585.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.704
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PBX1	NM_002585.4	c.192-150T>C		intron_variant	Intron 1 of 8	ENST00000420696.7	NP_002576.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PBX1	ENST00000420696.7	c.192-150T>C		intron_variant	Intron 1 of 8	1	NM_002585.4	ENSP00000405890.2

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43841 AN: 151794 Hom.: 8359 Cov.: 32

Gnomad AFR AF: 0.529

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.288

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.280

GnomAD4 exome AF: 0.203 AC: 71894 AN: 353868 Hom.: 9127 AF XY: 0.200 AC XY: 37665 AN XY: 188552

African (AFR) AF: 0.521 AC: 4778 AN: 9170

American (AMR) AF: 0.301 AC: 3939 AN: 13104

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 1782 AN: 10846

East Asian (EAS) AF: 0.415 AC: 10634 AN: 25620

South Asian (SAS) AF: 0.194 AC: 5299 AN: 27304

European-Finnish (FIN) AF: 0.116 AC: 3497 AN: 30196

Middle Eastern (MID) AF: 0.213 AC: 577 AN: 2710

European-Non Finnish (NFE) AF: 0.172 AC: 36825 AN: 214342

Other (OTH) AF: 0.222 AC: 4563 AN: 20576

GnomAD4 genome AF: 0.289 AC: 43934 AN: 151912 Hom.: 8387 Cov.: 32 AF XY: 0.287 AC XY: 21272 AN XY: 74246

African (AFR) AF: 0.530 AC: 21904 AN: 41346

American (AMR) AF: 0.288 AC: 4402 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 587 AN: 3466

East Asian (EAS) AF: 0.431 AC: 2218 AN: 5150

South Asian (SAS) AF: 0.211 AC: 1017 AN: 4820

European-Finnish (FIN) AF: 0.116 AC: 1224 AN: 10584

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.173 AC: 11738 AN: 67960

Other (OTH) AF: 0.285 AC: 603 AN: 2114

Alfa AF: 0.237 Hom.: 9906

Bravo AF: 0.311

Asia WGS AF: 0.364 AC: 1263 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Benign	0.78
PhyloP100		0.70
PromoterAI		-0.0033	Neutral
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: rs4657364; hg19: chr1-164532325;