9-125747625-G-C

Variant names:

• chr9-125747625-G-C
• rs1836227956
• NM_006195.6:c.172G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_006195.6(PBX3):​c.172G>C​(p.Asp58His) variant causes a missense change. The variant allele was found at a frequency of 0.00000761 in 1,445,714 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: 29)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: PBX3 NM_006195.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.99
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.748
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006195.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PBX3	NM_006195.6	MANE Select	c.172G>C	p.Asp58His	missense	Exon 1 of 9	NP_006186.1	P40426-1
	PBX3	NM_001411009.1		c.172G>C	p.Asp58His	missense	Exon 1 of 10	NP_001397938.1	Q5JS98
	PBX3	NM_001330782.2		c.172G>C	p.Asp58His	missense	Exon 1 of 8	NP_001317711.1	P40426-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PBX3	ENST00000373489.10	TSL:1 MANE Select	c.172G>C	p.Asp58His	missense	Exon 1 of 9	ENSP00000362588.5	P40426-1
	PBX3	ENST00000373482.6	TSL:1	n.172G>C		non_coding_transcript_exon	Exon 1 of 8	ENSP00000362581.2	H3BLX0
	PBX3	ENST00000373492.6	TSL:1	n.172G>C		non_coding_transcript_exon	Exon 1 of 7	ENSP00000362591.2	H3BLX0

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000761 AC: 11 AN: 1445714 Hom.: 0 Cov.: 32 AF XY: 0.00000556 AC XY: 4 AN XY: 719378

African (AFR) AF: 0.00 AC: 0 AN: 31480

American (AMR) AF: 0.00 AC: 0 AN: 43214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25642

East Asian (EAS) AF: 0.00 AC: 0 AN: 37344

South Asian (SAS) AF: 0.00 AC: 0 AN: 84760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00000996 AC: 11 AN: 1104550

Other (OTH) AF: 0.00 AC: 0 AN: 59740

GnomAD4 genome Cov.: 29

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.075	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.30
Sift	Benign	0.037	D
Sift4G	Benign	0.17	T
Polyphen		0.94	P
Vest4		0.62
MutPred		0.82		Loss of disorder (P = 0.1481)
MVP		0.46
MPC		1.3
ClinPred		0.99	D
GERP RS		2.4
PromoterAI		-0.15	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.47
Mutation Taster		=249/51	polymorphism

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

Other links and lift over

dbSNP: rs1836227956; hg19: chr9-128509904;