Genetic Variant NM_025245.3:c.953G>A (chr19-19563588-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_025245.3(PBX4):c.953G>A(p.Ser318Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PBX4
NM_025245.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.28

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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06502023).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PBX4	NM_025245.3 link	c.953G>A	p.Ser318Asn	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.953G>A	p.Ser318Asn	missense_variant	Exon 7 of 8	1	NM_025245.3	ENSP00000251203.5	Q9BYU1
PBX4	ENST00000557978.6 link	n.*511G>A		non_coding_transcript_exon_variant	Exon 7 of 8	1		ENSP00000453348.1	H0YL59
PBX4	ENST00000557978.6 link	n.*511G>A		3_prime_UTR_variant	Exon 7 of 8	1		ENSP00000453348.1	H0YL59
PBX4	ENST00000558276.7 link	n.237G>A		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1397964

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

689524

African (AFR)

AF:

0.00

AC:

AN:

31700

American (AMR)

AF:

0.00

AC:

AN:

35698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25176

East Asian (EAS)

AF:

0.00

AC:

AN:

36048

South Asian (SAS)

AF:

0.00

AC:

AN:

79214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48930

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4250

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079086

Other (OTH)

AF:

0.00

AC:

AN:

57862

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

Oct 02, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.953G>A (p.S318N) 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 953, causing the serine (S) at amino acid position 318 to be replaced by an asparagine (N). 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

0.097

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

6.7

(source)

DANN

Benign

0.12

DEOGEN2

Benign

0.0074

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.63

M_CAP

Benign

0.021

MetaRNN

Benign

0.065

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.77

PhyloP100

3.3

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.090

REVEL

Benign

0.15

Sift

Benign

1.0

Sift4G

Benign

0.79

Polyphen

0.0020

Vest4

0.074

MutPred

0.21

Loss of phosphorylation at S318 (P = 0.0516);

MVP

0.86

MPC

0.14

ClinPred

0.31

GERP RS

0.96

Varity_R

0.033

gMVP

0.18

Mutation Taster

=94/6

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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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