9-125962194-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006195.6(PBX3):c.1102G>A(p.Gly368Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PBX3 NM_006195.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.55

Genes affected

PBX3 (HGNC:8634): (PBX homeobox 3) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in animal organ development; neuron development; and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including adult locomotory behavior; dorsal spinal cord development; and regulation of respiratory gaseous exchange by nervous system process. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PBX3	NM_006195.6	c.1102G>A	p.Gly368Arg	missense_variant	7/9	ENST00000373489.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PBX3	ENST00000373489.10	c.1102G>A	p.Gly368Arg	missense_variant	7/9	1	NM_006195.6	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453434 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 723606

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: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2021

The c.1102G>A (p.G368R) alteration is located in exon 7 (coding exon 7) of the PBX3 gene. This alteration results from a G to A substitution at nucleotide position 1102, causing the glycine (G) at amino acid position 368 to be replaced by an arginine (R). 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	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.13	T;T;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Uncertain	0.75	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.5	D;D;N
REVEL	Uncertain	0.64
Sift	Uncertain	0.0030	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;B;.
Vest4		0.83
MutPred		0.37		Gain of MoRF binding (P = 0.0504);.;.;
MVP		0.90
MPC		0.24
ClinPred		0.87	D
GERP RS		5.8
Varity_R		0.20
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1842445008; hg19: chr9-128724473; COSMIC: COSV60731162;