Genetic Variant NM_025245.3:c.1020C>G (chr19-19563521-G-C) – 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.1020C>G(p.Cys340Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,395,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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: 0.000010 ( 0 hom. )

Consequence

PBX4
NM_025245.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.573

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=0.17169559).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PBX4	NM_025245.3 link	c.1020C>G	p.Cys340Trp	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.1020C>G	p.Cys340Trp	missense_variant	Exon 7 of 8	1	NM_025245.3	ENSP00000251203.5	Q9BYU1
PBX4	ENST00000557978.6 link	n.*578C>G		non_coding_transcript_exon_variant	Exon 7 of 8	1		ENSP00000453348.1	H0YL59
PBX4	ENST00000557978.6 link	n.*578C>G		3_prime_UTR_variant	Exon 7 of 8	1		ENSP00000453348.1	H0YL59
PBX4	ENST00000558276.7 link	n.304C>G		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000100

AC:

AN:

1395216

Hom.:

Cov.:

AF XY:

0.00000872

AC XY:

AN XY:

688004

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31570

American (AMR)

AF:

0.00

AC:

AN:

35504

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25140

East Asian (EAS)

AF:

0.00

AC:

AN:

35782

South Asian (SAS)

AF:

0.00

AC:

AN:

78744

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48834

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4950

European-Non Finnish (NFE)

AF:

0.0000121

AC:

AN:

1076848

Other (OTH)

AF:

0.0000173

AC:

AN:

57844

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.418

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 30, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1020C>G (p.C340W) alteration is located in exon 7 (coding exon 7) of the PBX4 gene. This alteration results from a C to G substitution at nucleotide position 1020, causing the cysteine (C) at amino acid position 340 to be replaced by a tryptophan (W). 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

0.11

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.025

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.41

M_CAP

Benign

0.028

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.36

MutationAssessor

Benign

1.2

PhyloP100

0.57

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.99

REVEL

Benign

0.26

Sift

Benign

0.18

Sift4G

Benign

0.17

Polyphen

0.82

Vest4

0.19

MutPred

0.14

Loss of catalytic residue at L341 (P = 0.0295);

MVP

0.90

MPC

0.34

ClinPred

0.34

GERP RS

-0.37

Varity_R

0.097

gMVP

0.39

Mutation Taster

=84/16

polymorphism

(source)

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

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NM_025245.3:c.1020C>G

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