1-164559935-G-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1PP2BP4_StrongBS1_SupportingBS2

The NM_002585.4(PBX1):c.113G>A(p.Gly38Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000711 in 1,547,548 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 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000057 ( 0 hom. )

Consequence

PBX1
NM_002585.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.93

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1

In a domain PBC (size 194) in uniprot entity PBX1_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_002585.4

PP2

Missense variant in the PBX1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 3.8266 (above the threshold of 3.09). Trascript score misZ: 4.2973 (above the threshold of 3.09). GenCC associations: The gene is linked to congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay.

BP4

Computational evidence support a benign effect (MetaRNN=0.01794511).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000197 (3/152142) while in subpopulation AMR AF= 0.000131 (2/15284). AF 95% confidence interval is 0.0000226. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PBX1	NM_002585.4 link	c.113G>A	p.Gly38Glu	missense_variant	Exon 1 of 9	ENST00000420696.7	NP_002576.1	P40424-1A1MJ41A8K5V0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PBX1	ENST00000420696.7 link	c.113G>A	p.Gly38Glu	missense_variant	Exon 1 of 9	1	NM_002585.4	ENSP00000405890.2		P40424-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000463

AC:

AN:

151082

Hom.:

AF XY:

0.0000126

AC XY:

AN XY:

79638

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000573

AC:

AN:

1395406

Hom.:

Cov.:

AF XY:

0.00000291

AC XY:

AN XY:

687986

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000227

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000123

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jun 21, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.113G>A (p.G38E) alteration is located in exon 1 (coding exon 1) of the PBX1 gene. This alteration results from a G to A substitution at nucleotide position 113, causing the glycine (G) at amino acid position 38 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Jul 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 38 of the PBX1 protein (p.Gly38Glu). This variant is present in population databases (rs370561885, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PBX1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Benign

0.74

DEOGEN2

Benign

0.096

T;T;T;.;.;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.47

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.88

D;D;D;D;D;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.018

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

.;.;L;L;L;.

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.78

.;N;N;.;N;N

REVEL

Benign

0.29

Sift

Benign

0.45

.;T;T;.;T;T

Sift4G

Benign

0.21

T;T;T;T;T;T

Polyphen

0.036

.;.;B;.;.;.

Vest4

0.47

MVP

0.50

MPC

0.17

ClinPred

0.085

GERP RS

3.6

Varity_R

0.14

gMVP

0.40

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