NM_002585.4:c.266-12037G>A

Variant names:

• chr1-164780457-G-A
• rs9661977
• NM_002585.4:c.266-12037G>A

Variant summary

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

The NM_002585.4(PBX1):​c.266-12037G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 152,036 control chromosomes in the GnomAD database, including 4,007 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 0.22 (4007 hom., cov: 32)
• Consequence: PBX1 NM_002585.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.512
• 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: 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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PBX1	NM_002585.4	c.266-12037G>A		intron_variant	Intron 2 of 8	ENST00000420696.7	NP_002576.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PBX1	ENST00000420696.7	c.266-12037G>A		intron_variant	Intron 2 of 8	1	NM_002585.4	ENSP00000405890.2

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34068 AN: 151916 Hom.: 4003 Cov.: 32

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.300

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.213

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.224 AC: 34100 AN: 152036 Hom.: 4007 Cov.: 32 AF XY: 0.229 AC XY: 16983 AN XY: 74300

African (AFR) AF: 0.237 AC: 9829 AN: 41442

American (AMR) AF: 0.161 AC: 2464 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 545 AN: 3466

East Asian (EAS) AF: 0.147 AC: 760 AN: 5174

South Asian (SAS) AF: 0.263 AC: 1269 AN: 4826

European-Finnish (FIN) AF: 0.300 AC: 3169 AN: 10556

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.226 AC: 15356 AN: 67984

Other (OTH) AF: 0.219 AC: 462 AN: 2112

Alfa AF: 0.227 Hom.: 466

Bravo AF: 0.211

Asia WGS AF: 0.232 AC: 802 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.8
DANN	Benign	0.71
PhyloP100		-0.51
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: rs9661977; hg19: chr1-164749694;