rs2275558

Variant names:

• chr1-164559883-G-A
• rs2275558
• NM_002585.4:c.61G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-164559883-G-A
• chr1-164559883-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_002585.4(PBX1):​c.61G>A​(p.Gly21Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,550,066 control chromosomes in the GnomAD database, including 51,948 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (4494 hom., cov: 31)
  • Exomes 𝑓: 0.24 (47454 hom.)
• Consequence: PBX1 NM_002585.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 8.01
• Publications: 44 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Illumina, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• 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=2.8911233E-4).
• BP6: Variant 1-164559883-G-A is Benign according to our data. Variant chr1-164559883-G-A is described in ClinVar as Benign. ClinVar VariationId is 1288942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

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.61G>A	p.Gly21Ser	missense	Exon 1 of 9	NP_002576.1
	PBX1	NM_001204963.2		c.61G>A	p.Gly21Ser	missense	Exon 1 of 9	NP_001191892.1
	PBX1	NM_001204961.2		c.61G>A	p.Gly21Ser	missense	Exon 1 of 8	NP_001191890.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PBX1	ENST00000420696.7	TSL:1 MANE Select	c.61G>A	p.Gly21Ser	missense	Exon 1 of 9	ENSP00000405890.2
	PBX1	ENST00000367897.5	TSL:1	c.61G>A	p.Gly21Ser	missense	Exon 1 of 8	ENSP00000356872.1
	PBX1	ENST00000627490.2	TSL:2	c.61G>A	p.Gly21Ser	missense	Exon 1 of 9	ENSP00000485692.1

Frequencies

GnomAD3 genomes AF: 0.204 AC: 30976 AN: 151828 Hom.: 4492 Cov.: 31

Gnomad AFR AF: 0.0447

Gnomad AMI AF: 0.278

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.631

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.211

GnomAD2 exomes AF: 0.304 AC: 46889 AN: 154030 AF XY: 0.304

Gnomad AFR exome AF: 0.0372

Gnomad AMR exome AF: 0.477

Gnomad ASJ exome AF: 0.245

Gnomad EAS exome AF: 0.632

Gnomad FIN exome AF: 0.208

Gnomad NFE exome AF: 0.217

Gnomad OTH exome AF: 0.256

GnomAD4 exome AF: 0.241 AC: 336771 AN: 1398128 Hom.: 47454 Cov.: 37 AF XY: 0.245 AC XY: 168880 AN XY: 689538

African (AFR) AF: 0.0357 AC: 1127 AN: 31558

American (AMR) AF: 0.466 AC: 16585 AN: 35624

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 6111 AN: 25154

East Asian (EAS) AF: 0.679 AC: 24163 AN: 35606

South Asian (SAS) AF: 0.376 AC: 29793 AN: 79148

European-Finnish (FIN) AF: 0.207 AC: 10169 AN: 49220

Middle Eastern (MID) AF: 0.179 AC: 971 AN: 5436

European-Non Finnish (NFE) AF: 0.217 AC: 233695 AN: 1078478

Other (OTH) AF: 0.244 AC: 14157 AN: 57904

GnomAD4 genome AF: 0.204 AC: 30981 AN: 151938 Hom.: 4494 Cov.: 31 AF XY: 0.213 AC XY: 15845 AN XY: 74236

African (AFR) AF: 0.0446 AC: 1854 AN: 41530

American (AMR) AF: 0.360 AC: 5499 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 812 AN: 3466

East Asian (EAS) AF: 0.632 AC: 3212 AN: 5080

South Asian (SAS) AF: 0.378 AC: 1814 AN: 4796

European-Finnish (FIN) AF: 0.212 AC: 2243 AN: 10558

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14785 AN: 67944

Other (OTH) AF: 0.211 AC: 443 AN: 2100

Alfa AF: 0.230 Hom.: 8688

Bravo AF: 0.209

TwinsUK AF: 0.218 AC: 808

ALSPAC AF: 0.214 AC: 825

ESP6500AA AF: 0.0408 AC: 168

ESP6500EA AF: 0.188 AC: 1503

ExAC AF: 0.171 AC: 12421

Asia WGS AF: 0.448 AC: 1555 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.011
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.00029	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.0	L
PhyloP100		8.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.31
Sift	Benign	0.12	T
Sift4G	Benign	0.083	T
Polyphen		0.49	P
Vest4		0.43
MPC		0.050
ClinPred		0.043	T
GERP RS		5.2
PromoterAI		-0.070	Neutral
Varity_R		0.12
gMVP		0.46
Mutation Taster		=97/3	polymorphism (auto)

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: rs2275558; hg19: chr1-164529120; COSMIC: COSV61532892; COSMIC: COSV61532892;