Genetic Variant PBX1:c.266-22560T>C (chr1-164769934-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002585.4(PBX1):c.266-22560T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.71 in 151,982 control chromosomes in the GnomAD database, including 38,866 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 0.71 ( 38863 hom., cov: 31)

Exomes 𝑓: 0.71 ( 3 hom. )

Consequence

PBX1
NM_002585.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.71

Publications

16 publications found

Variant links:

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 links:

PBX1-AS1 (HGNC:40425): (PBX1 antisense RNA 1)

PBX1-AS1 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.824 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PBX1	NM_002585.4	MANE Select	c.266-22560T>C	intron	N/A	NP_002576.1
PBX1-AS1	NR_038072.1		n.1647A>G	non_coding_transcript_exon	Exon 3 of 4
PBX1	NM_001204963.2		c.266-22560T>C	intron	N/A	NP_001191892.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PBX1	ENST00000420696.7	TSL:1 MANE Select	c.266-22560T>C	intron	N/A	ENSP00000405890.2
PBX1	ENST00000367897.5	TSL:1	c.266-22560T>C	intron	N/A	ENSP00000356872.1
PBX1-AS1	ENST00000421530.1	TSL:2	n.1647A>G	non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes

AF:

0.710

AC:

107857

AN:

151850

Hom.:

38832

Cov.:

show subpopulations

Gnomad AFR

AF:

0.622

Gnomad AMI

AF:

0.711

Gnomad AMR

AF:

0.620

Gnomad ASJ

AF:

0.591

Gnomad EAS

AF:

0.732

Gnomad SAS

AF:

0.845

Gnomad FIN

AF:

0.775

Gnomad MID

AF:

0.775

Gnomad NFE

AF:

0.769

Gnomad OTH

AF:

0.712

GnomAD4 exome

AF:

0.714

AC:

AN:

Hom.:

Cov.:

AF XY:

0.833

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.750

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000546988), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.710

AC:

107937

AN:

151968

Hom.:

38863

Cov.:

AF XY:

0.710

AC XY:

52761

AN XY:

74280

show subpopulations

African (AFR)

AF:

0.623

AC:

25770

AN:

41394

American (AMR)

AF:

0.619

AC:

9457

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.591

AC:

2052

AN:

3470

East Asian (EAS)

AF:

0.732

AC:

3747

AN:

5120

South Asian (SAS)

AF:

0.846

AC:

4081

AN:

4826

European-Finnish (FIN)

AF:

0.775

AC:

8191

AN:

10572

Middle Eastern (MID)

AF:

0.772

AC:

227

AN:

294

European-Non Finnish (NFE)

AF:

0.769

AC:

52262

AN:

67992

Other (OTH)

AF:

0.712

AC:

1502

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1550

3101

4651

6202

7752

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

832

1664

2496

3328

4160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.744

Hom.:

175925

Bravo

AF:

0.691

Asia WGS

AF:

0.775

AC:

2696

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.41

(source)

DANN

Benign

0.73

PhyloP100

-1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over