1-164559941-A-G

Variant names:

• chr1-164559941-A-G
• NM_002585.4:c.119A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_002585.4(PBX1):​c.119A>G​(p.Lys40Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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: PBX1 NM_002585.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.16

Genes affected

PBX1 (HGNC:8632): (PBX homeobox 1) This gene encodes a nuclear protein that belongs to the PBX homeobox family of transcriptional factors. Studies in mice suggest that this gene may be involved in the regulation of osteogenesis and required for skeletal patterning and programming. A chromosomal translocation, t(1;19) involving this gene and TCF3/E2A gene, is associated with pre-B-cell acute lymphoblastic leukemia. The resulting fusion protein, in which the DNA binding domain of E2A is replaced by the DNA binding domain of this protein, transforms cells by constitutively activating transcription of genes regulated by the PBX protein family. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain PBC (size 194) in uniprot entity PBX1_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_002585.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the PBX1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 3.8266 (above the threshold of 3.09). Trascript score misZ: 4.2973 (above the threshold of 3.09). GenCC associations: The gene is linked to congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay.
• BP4: Computational evidence support a benign effect (MetaRNN=0.27704284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PBX1	NM_002585.4	c.119A>G	p.Lys40Arg	missense_variant	Exon 1 of 9	ENST00000420696.7	NP_002576.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PBX1	ENST00000420696.7	c.119A>G	p.Lys40Arg	missense_variant	Exon 1 of 9	1	NM_002585.4	ENSP00000405890.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1395550 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 687978

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay Uncertain:1

Apr 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T;T;.;.;T
Eigen	Benign	-0.053
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.28	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	.;.;L;L;L;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.1	.;N;N;.;N;N
REVEL	Benign	0.22
Sift	Benign	0.25	.;T;T;.;T;T
Sift4G	Benign	0.10	T;T;T;T;T;T
Polyphen		0.041	.;.;B;.;.;.
Vest4		0.67
MutPred		0.39		Loss of ubiquitination at K40 (P = 0.0059);Loss of ubiquitination at K40 (P = 0.0059);Loss of ubiquitination at K40 (P = 0.0059);Loss of ubiquitination at K40 (P = 0.0059);Loss of ubiquitination at K40 (P = 0.0059);Loss of ubiquitination at K40 (P = 0.0059);
MVP		0.59
MPC		0.049
ClinPred		0.70	D
GERP RS		5.4
Varity_R		0.18
gMVP		0.16

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-164529178;