Genetic Variant PBX3:p.Glu86* (chr9-125748605-G-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_006195.6(PBX3):c.256G>T(p.Glu86*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PBX3
NM_006195.6 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.78

Publications

0 publications found

Variant links:

Genes affected

PBX3 (HGNC:8634): (PBX homeobox 3) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in animal organ development; neuron development; and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including adult locomotory behavior; dorsal spinal cord development; and regulation of respiratory gaseous exchange by nervous system process. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

PBX3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006195.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PBX3	NM_006195.6	MANE Select	c.256G>T	p.Glu86*	stop_gained	Exon 2 of 9	NP_006186.1	P40426-1
PBX3	NM_001411009.1		c.256G>T	p.Glu86*	stop_gained	Exon 2 of 10	NP_001397938.1	Q5JS98
PBX3	NM_001134778.2		c.31G>T	p.Glu11*	stop_gained	Exon 2 of 9	NP_001128250.1	P40426-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PBX3	ENST00000373489.10	TSL:1 MANE Select	c.256G>T	p.Glu86*	stop_gained	Exon 2 of 9	ENSP00000362588.5	P40426-1
PBX3	ENST00000447726.6	TSL:1	c.31G>T	p.Glu11*	stop_gained	Exon 2 of 9	ENSP00000387456.2	P40426-5
PBX3	ENST00000373482.6	TSL:1	n.256G>T		non_coding_transcript_exon	Exon 2 of 8	ENSP00000362581.2	H3BLX0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461166

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726940

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

52914

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111838

Other (OTH)

AF:

0.00

AC:

AN:

60376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000983081), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Uncertain

0.96

PhyloP100

7.8

Vest4

0.93

GERP RS

5.2

PromoterAI

-0.053

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Mutation Taster

=7/193

disease causing (fs/PTC)

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over