1-154945725-C-T

Variant names:

• chr1-154945725-C-T
• rs745435353
• NM_020524.4:c.1949G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.35

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]

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=0.13622403).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PBXIP1	NM_020524.4	c.1949G>A	p.Arg650His	missense_variant	Exon 10 of 11	ENST00000368463.8	NP_065385.2
PBXIP1	NM_001317734.2	c.1862G>A	p.Arg621His	missense_variant	Exon 9 of 10		NP_001304663.1
PBXIP1	NM_001317735.2	c.1484G>A	p.Arg495His	missense_variant	Exon 7 of 8		NP_001304664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PBXIP1	ENST00000368463.8	c.1949G>A	p.Arg650His	missense_variant	Exon 10 of 11	1	NM_020524.4	ENSP00000357448.3
PBXIP1	ENST00000368465.5	c.1862G>A	p.Arg621His	missense_variant	Exon 9 of 10	2		ENSP00000357450.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152228 Hom.: 0 Cov.: 32

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

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

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

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

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

Other links and lift over

dbSNP: rs745435353; hg19: chr1-154918201;