Variant 9-125747475-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_006195.6(PBX3):c.22C>G(p.Leu8Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000099 in 1,576,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00042 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

PBX3
NM_006195.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.289

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 made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.029993981).

BS2

High AC in GnomAd at 63 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PBX3	NM_006195.6 linkuse as main transcript	c.22C>G	p.Leu8Val	missense_variant	1/9	ENST00000373489.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PBX3	ENST00000373489.10 linkuse as main transcript	c.22C>G	p.Leu8Val	missense_variant	1/9	1	NM_006195.6	A1	P40426-1

Frequencies

GnomAD3 genomes

AF:

0.000418

AC:

AN:

150618

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000460

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.000962

GnomAD3 exomes

AF:

0.000153

AC:

AN:

202416

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

111668

show subpopulations

Gnomad AFR exome

AF:

0.00110

Gnomad AMR exome

AF:

0.000505

Gnomad ASJ exome

AF:

0.000115

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000333

Gnomad OTH exome

AF:

0.000210

GnomAD4 exome

AF:

0.0000652

AC:

AN:

1425532

Hom.:

Cov.:

AF XY:

0.0000579

AC XY:

AN XY:

708620

show subpopulations

Gnomad4 AFR exome

AF:

0.00147

Gnomad4 AMR exome

AF:

0.000463

Gnomad4 ASJ exome

AF:

0.0000401

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000121

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000128

Gnomad4 OTH exome

AF:

0.000238

GnomAD4 genome

AF:

0.000418

AC:

AN:

150618

Hom.:

Cov.:

AF XY:

0.000394

AC XY:

AN XY:

73542

show subpopulations

Gnomad4 AFR

AF:

0.00129

Gnomad4 AMR

AF:

0.000460

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.000962

Alfa

AF:

0.000198

Hom.:

Bravo

AF:

0.000586

ESP6500AA

AF:

0.00137

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000133

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2024

The c.22C>G (p.L8V) alteration is located in exon 1 (coding exon 1) of the PBX3 gene. This alteration results from a C to G substitution at nucleotide position 22, causing the leucine (L) at amino acid position 8 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.28

Cadd

Benign

Dann

Uncertain

0.98

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Pathogenic

0.87

MetaRNN

Benign

0.030

T;T;T

MetaSVM

Benign

-0.53

MutationAssessor

Benign

0.0

N;.;N

MutationTaster

Benign

0.98

D;D;D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.49

N;N;N

REVEL

Benign

0.18

Sift

Uncertain

0.010

D;D;D

Sift4G

Uncertain

0.035

D;D;T

Polyphen

0.0020

.;.;B

Vest4

0.33

MVP

0.45

MPC

0.41

ClinPred

0.036

GERP RS

2.1

Varity_R

0.14

gMVP

0.19

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over