19-19618589-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025245.3(PBX4):c.41C>G(p.Pro14Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000963 in 1,142,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: PBX4 NM_025245.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.88

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1461035).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PBX4	NM_025245.3	c.41C>G	p.Pro14Arg	missense_variant	1/8	ENST00000251203.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PBX4	ENST00000251203.14	c.41C>G	p.Pro14Arg	missense_variant	1/8	1	NM_025245.3	P1
PBX4	ENST00000557978.6	c.41C>G	p.Pro14Arg	missense_variant, NMD_transcript_variant	1/8	1
PBX4	ENST00000558222.1	c.41C>G	p.Pro14Arg	missense_variant, NMD_transcript_variant	1/6	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000963 AC: 11 AN: 1142646 Hom.: 0 Cov.: 30 AF XY: 0.00000907 AC XY: 5 AN XY: 551432

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000116

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Dec 20, 2023

The c.41C>G (p.P14R) alteration is located in exon 1 (coding exon 1) of the PBX4 gene. This alteration results from a C to G substitution at nucleotide position 41, causing the proline (P) at amino acid position 14 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	-0.030	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	15
Dann	Benign	0.65
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.34	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.11
Sift	Benign	0.20	T
Sift4G	Benign	0.40	T
Polyphen		0.012	B
Vest4		0.19
MutPred		0.32		Loss of glycosylation at P14 (P = 0.0103);
MVP		0.80
MPC		0.16
ClinPred		0.15	T
GERP RS		1.0
Varity_R		0.039
gMVP		0.44

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-19729398;