rs4282786

Variant names:

• chr1-214003526-G-A
• rs4282786
• NM_001270616.2:c.1726-1639G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001270616.2(PROX1):​c.1726-1639G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 152,052 control chromosomes in the GnomAD database, including 6,012 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.28 (6012 hom., cov: 33)
• Consequence: PROX1 NM_001270616.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.15
• Publications: 6 publications found

Genes affected

PROX1 (HGNC:9459): (prospero homeobox 1) The protein encoded by this gene is a member of the homeobox transcription factor family. Members of this family contain a homeobox domain that consists of a 60-amino acid helix-turn-helix structure that binds DNA and RNA. The protein encoded by this gene is conserved across vertebrates and may play an essential role during development. Altered levels of this protein have been reported in cancers of different organs, such as colon, brain, blood, breast, pancreas, liver and esophagus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2012]

PROX1 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270616.2. 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
	PROX1	NM_001270616.2	MANE Select	c.1726-1639G>A		intron	N/A	NP_001257545.1	Q92786
	PROX1	NM_002763.5		c.1726-1639G>A		intron	N/A	NP_002754.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROX1	ENST00000366958.9	TSL:1 MANE Select	c.1726-1639G>A		intron	N/A	ENSP00000355925.4	Q92786
	PROX1	ENST00000435016.2	TSL:1	c.1726-1639G>A		intron	N/A	ENSP00000400694.1	Q92786
	PROX1	ENST00000881021.1		c.1726-1639G>A		intron	N/A	ENSP00000551080.1

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41946 AN: 151934 Hom.: 6000 Cov.: 33

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.268

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.281

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.276 AC: 42006 AN: 152052 Hom.: 6012 Cov.: 33 AF XY: 0.278 AC XY: 20674 AN XY: 74330

African (AFR) AF: 0.270 AC: 11210 AN: 41470

American (AMR) AF: 0.390 AC: 5963 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.268 AC: 928 AN: 3468

East Asian (EAS) AF: 0.314 AC: 1629 AN: 5182

South Asian (SAS) AF: 0.163 AC: 782 AN: 4806

European-Finnish (FIN) AF: 0.283 AC: 2990 AN: 10560

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.260 AC: 17680 AN: 67968

Other (OTH) AF: 0.283 AC: 598 AN: 2116

Alfa AF: 0.271 Hom.: 1985

Bravo AF: 0.287

Asia WGS AF: 0.292 AC: 1016 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	16
DANN	Benign	0.73
PhyloP100		2.2
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4282786;

hg19: chr1-214176869;