Genetic Variant NM_025245.3:c.79A>C (chr19-19618551-T-G) – 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.79A>C(p.Met27Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000758 in 1,451,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000077 ( 0 hom. )

Consequence

PBX4
NM_025245.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.26

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:

Genome browser will be placed here

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=0.13650656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PBX4	NM_025245.3 link	c.79A>C	p.Met27Leu	missense_variant	Exon 1 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.79A>C	p.Met27Leu	missense_variant	Exon 1 of 8	1	NM_025245.3	ENSP00000251203.5	Q9BYU1
PBX4	ENST00000557978.6 link	n.79A>C		non_coding_transcript_exon_variant	Exon 1 of 8	1		ENSP00000453348.1	H0YL59
PBX4	ENST00000558222.1 link	n.79A>C		non_coding_transcript_exon_variant	Exon 1 of 6	2		ENSP00000453069.1	H0YL59

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000153

AC:

AN:

130518

AF XY:

0.0000269

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000167

Gnomad OTH exome

AF:

0.000349

GnomAD4 exome

AF:

0.00000770

AC:

AN:

1299460

Hom.:

Cov.:

AF XY:

0.00000933

AC XY:

AN XY:

643318

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27020

American (AMR)

AF:

0.00

AC:

AN:

26128

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21420

East Asian (EAS)

AF:

0.00

AC:

AN:

30666

South Asian (SAS)

AF:

0.00

AC:

AN:

64026

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46008

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3638

European-Non Finnish (NFE)

AF:

0.00000875

AC:

AN:

1028448

Other (OTH)

AF:

0.0000192

AC:

AN:

52106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67984

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000628

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000844

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 11, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.79A>C (p.M27L) alteration is located in exon 1 (coding exon 1) of the PBX4 gene. This alteration results from a A to C substitution at nucleotide position 79, causing the methionine (M) at amino acid position 27 to be replaced by a leucine (L). 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

0.25

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.058

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.54

FATHMM_MKL

Uncertain

0.78

LIST_S2

Pathogenic

0.97

M_CAP

Benign

0.0085

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

PhyloP100

1.3

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-2.1

REVEL

Benign

0.057

Sift

Benign

0.098

Sift4G

Benign

0.14

Polyphen

0.22

Vest4

0.25

MutPred

0.43

Loss of loop (P = 0.1258);

MVP

0.35

MPC

0.25

ClinPred

0.12

GERP RS

1.5

PromoterAI

-0.17

Neutral

(source)

Varity_R

0.28

gMVP

0.36

Mutation Taster

=84/16

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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