Genetic Variant NM_025245.3:c.1012G>A (chr19-19563529-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_025245.3(PBX4):c.1012G>A(p.Gly338Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,398,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

PBX4
NM_025245.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.51

Publications

0 publications found

Variant links:

Genes affected

PBX4 (HGNC:13403): (PBX homeobox 4) This gene encodes a member of the pre-B cell leukemia transcription factor family. These proteins are homeobox proteins that play critical roles in embryonic development and cellular differentiation both as Hox cofactors and through Hox-independent pathways. The encoded protein contains a homeobox DNA-binding domain, but specific functions of the protein have not been determined. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, May 2011]

PBX4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24802065).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PBX4	NM_025245.3 link	c.1012G>A	p.Gly338Arg	missense_variant	Exon 7 of 8	ENST00000251203.14	NP_079521.1	Q9BYU1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PBX4	ENST00000251203.14 link	c.1012G>A	p.Gly338Arg	missense_variant	Exon 7 of 8	1	NM_025245.3	ENSP00000251203.5	Q9BYU1
PBX4	ENST00000557978.6 link	n.*570G>A		non_coding_transcript_exon_variant	Exon 7 of 8	1		ENSP00000453348.1	H0YL59
PBX4	ENST00000557978.6 link	n.*570G>A		3_prime_UTR_variant	Exon 7 of 8	1		ENSP00000453348.1	H0YL59
PBX4	ENST00000558276.7 link	n.296G>A		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000286

AC:

AN:

1398086

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

689596

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31626

American (AMR)

AF:

0.00

AC:

AN:

35678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25162

East Asian (EAS)

AF:

0.00

AC:

AN:

35860

South Asian (SAS)

AF:

0.00

AC:

AN:

79174

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48916

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4922

European-Non Finnish (NFE)

AF:

0.00000371

AC:

AN:

1078832

Other (OTH)

AF:

0.00

AC:

AN:

57916

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 27, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1012G>A (p.G338R) alteration is located in exon 7 (coding exon 7) of the PBX4 gene. This alteration results from a G to A substitution at nucleotide position 1012, causing the glycine (G) at amino acid position 338 to be replaced by an arginine (R). 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

0.091

BayesDel_addAF

Benign

0.0048

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.66

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.49

M_CAP

Benign

0.012

MetaRNN

Benign

0.25

MetaSVM

Uncertain

0.19

MutationAssessor

Uncertain

2.1

PhyloP100

3.5

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.24

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0070

Polyphen

0.044

Vest4

0.25

MutPred

0.33

Gain of methylation at G338 (P = 0.0136);

MVP

0.89

MPC

0.19

ClinPred

0.85

GERP RS

2.2

Varity_R

0.16

gMVP

0.50

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over