19-19569483-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_025245.3(PBX4):c.734A>G(p.Glu245Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PBX4 NM_025245.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.18

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PBX4	NM_025245.3	c.734A>G	p.Glu245Gly	missense_variant	5/8	ENST00000251203.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PBX4	ENST00000251203.14	c.734A>G	p.Glu245Gly	missense_variant	5/8	1	NM_025245.3	P1
PBX4	ENST00000557978.6	c.*292A>G		3_prime_UTR_variant, NMD_transcript_variant	5/8	1
PBX4	ENST00000558222.1	c.*282A>G		3_prime_UTR_variant, NMD_transcript_variant	5/6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2021

The c.734A>G (p.E245G) alteration is located in exon 5 (coding exon 5) of the PBX4 gene. This alteration results from a A to G substitution at nucleotide position 734, causing the glutamic acid (E) at amino acid position 245 to be replaced by a glycine (G). 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	0.24
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.76	P
Vest4		0.68
MutPred		0.46		Gain of MoRF binding (P = 0.0725);
MVP		0.99
MPC		0.67
ClinPred		0.99	D
GERP RS		2.6
Varity_R		0.67
gMVP		0.66

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

LitVar

Other links and lift over

dbSNP: rs1414890336; hg19: chr19-19680292;