Genetic Variant PBX4:p.Asp321Tyr (chr19-19563580-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_025245.3(PBX4):c.961G>T(p.Asp321Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,398,066 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PBX4
NM_025245.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.17

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PBX4	NM_025245.3 link	c.961G>T	p.Asp321Tyr	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.961G>T	p.Asp321Tyr	missense_variant	Exon 7 of 8	1	NM_025245.3	ENSP00000251203.5	Q9BYU1
PBX4	ENST00000557978.6 link	n.*519G>T		non_coding_transcript_exon_variant	Exon 7 of 8	1		ENSP00000453348.1	H0YL59
PBX4	ENST00000557978.6 link	n.*519G>T		3_prime_UTR_variant	Exon 7 of 8	1		ENSP00000453348.1	H0YL59
PBX4	ENST00000558276.7 link	n.245G>T		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1398066

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

689580

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31704

American (AMR)

AF:

0.00

AC:

AN:

35692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25172

East Asian (EAS)

AF:

0.00

AC:

AN:

36078

South Asian (SAS)

AF:

0.00

AC:

AN:

79220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48928

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4314

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1079096

Other (OTH)

AF:

0.00

AC:

AN:

57862

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 21, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.961G>T (p.D321Y) alteration is located in exon 7 (coding exon 7) of the PBX4 gene. This alteration results from a G to T substitution at nucleotide position 961, causing the aspartic acid (D) at amino acid position 321 to be replaced by a tyrosine (Y). 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

0.14

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

Eigen

Benign

-0.044

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.43

M_CAP

Benign

0.049

MetaRNN

Uncertain

0.62

MetaSVM

Uncertain

-0.012

MutationAssessor

Uncertain

2.5

PhyloP100

4.2

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.32

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0060

Polyphen

0.95

Vest4

0.53

MutPred

0.21

Gain of glycosylation at P317 (P = 0.1347);

MVP

0.92

MPC

0.67

ClinPred

0.96

GERP RS

1.9

Varity_R

0.21

gMVP

0.70

Mutation Taster

=88/12

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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chr19-19563580-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over