1-154945725-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020524.4(PBXIP1):​c.1949G>A​(p.Arg650His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,614,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

PBXIP1
NM_020524.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.35
Variant links:
Genes affected
PBXIP1 (HGNC:21199): (PBX homeobox interacting protein 1) The protein encoded by this gene interacts with the PBX1 homeodomain protein, inhibiting its transcriptional activation potential by preventing its binding to DNA. The encoded protein, which is primarily cytosolic but can shuttle to the nucleus, also can interact with estrogen receptors alpha and beta and promote the proliferation of breast cancer, brain tumors, and lung cancer. Several transcript variants encoding different isoforms have been found for this gene. More variants exist, but their full-length natures have yet to be determined. [provided by RefSeq, Dec 2015]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.13622403).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PBXIP1NM_020524.4 linkc.1949G>A p.Arg650His missense_variant Exon 10 of 11 ENST00000368463.8 NP_065385.2 Q96AQ6-1
PBXIP1NM_001317734.2 linkc.1862G>A p.Arg621His missense_variant Exon 9 of 10 NP_001304663.1 Q96AQ6-2
PBXIP1NM_001317735.2 linkc.1484G>A p.Arg495His missense_variant Exon 7 of 8 NP_001304664.1 Q96AQ6B4E0K4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PBXIP1ENST00000368463.8 linkc.1949G>A p.Arg650His missense_variant Exon 10 of 11 1 NM_020524.4 ENSP00000357448.3 Q96AQ6-1
PBXIP1ENST00000368465.5 linkc.1862G>A p.Arg621His missense_variant Exon 9 of 10 2 ENSP00000357450.1 Q96AQ6-2

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152228
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000132
AC:
33
AN:
250562
Hom.:
0
AF XY:
0.0000886
AC XY:
12
AN XY:
135494
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000752
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000139
Gnomad NFE exome
AF:
0.0000266
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000390
AC:
57
AN:
1461886
Hom.:
0
Cov.:
34
AF XY:
0.0000330
AC XY:
24
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000693
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.000187
Gnomad4 NFE exome
AF:
0.0000117
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152228
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000756
ExAC
AF:
0.0000988
AC:
12

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 06, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1949G>A (p.R650H) alteration is located in exon 10 (coding exon 9) of the PBXIP1 gene. This alteration results from a G to A substitution at nucleotide position 1949, causing the arginine (R) at amino acid position 650 to be replaced by a histidine (H). 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
0.12
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.44
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.037
.;T
Eigen
Benign
-0.0023
Eigen_PC
Benign
0.090
FATHMM_MKL
Benign
0.66
D
LIST_S2
Benign
0.82
T;T
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.14
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.9
.;L
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-2.2
N;N
REVEL
Benign
0.055
Sift
Benign
0.13
T;T
Sift4G
Uncertain
0.0080
D;D
Polyphen
0.39
.;B
Vest4
0.34
MutPred
0.34
.;Gain of loop (P = 0.1069);
MVP
0.40
MPC
0.27
ClinPred
0.090
T
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.072
gMVP
0.28

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs745435353; hg19: chr1-154918201; API