chr1-164559873-C-G

Variant names:

• chr1-164559873-C-G
• rs1057295149
• NM_002585.4:c.51C>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_002585.4(PBX1):​c.51C>G​(p.Ala17Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,398,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. A17A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: PBX1 NM_002585.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.860
• Publications: 0 publications found

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]

PBX1 Gene-Disease associations (from GenCC):

• congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Illumina, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 1-164559873-C-G is Benign according to our data. Variant chr1-164559873-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3625104.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.86 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 26 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002585.4. 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
	PBX1	NM_002585.4	MANE Select	c.51C>G	p.Ala17Ala	synonymous	Exon 1 of 9	NP_002576.1	P40424-1
	PBX1	NM_001204963.2		c.51C>G	p.Ala17Ala	synonymous	Exon 1 of 9	NP_001191892.1	P40424-3
	PBX1	NM_001204961.2		c.51C>G	p.Ala17Ala	synonymous	Exon 1 of 8	NP_001191890.1	Q53YC7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PBX1	ENST00000420696.7	TSL:1 MANE Select	c.51C>G	p.Ala17Ala	synonymous	Exon 1 of 9	ENSP00000405890.2	P40424-1
	PBX1	ENST00000367897.5	TSL:1	c.51C>G	p.Ala17Ala	synonymous	Exon 1 of 8	ENSP00000356872.1	P40424-2
	PBX1	ENST00000627490.2	TSL:2	c.51C>G	p.Ala17Ala	synonymous	Exon 1 of 9	ENSP00000485692.1	P40424-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000130 AC: 2 AN: 154434 AF XY: 0.0000244

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000168

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000186 AC: 26 AN: 1398080 Hom.: 0 Cov.: 31 AF XY: 0.0000160 AC XY: 11 AN XY: 689502

African (AFR) AF: 0.00 AC: 0 AN: 31542

American (AMR) AF: 0.00 AC: 0 AN: 35666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25146

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35652

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49118

Middle Eastern (MID) AF: 0.000188 AC: 1 AN: 5306

European-Non Finnish (NFE) AF: 0.0000213 AC: 23 AN: 1078586

Other (OTH) AF: 0.00 AC: 0 AN: 57886

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	12
DANN	Benign	0.73
PhyloP100		-0.86
PromoterAI		-0.066	Neutral
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1057295149; hg19: chr1-164529110;