rs4655480

Variant names:

• chr1-214007908-G-A
• rs4655480
• NM_001270616.2:c.1833+2636G>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.1833+2636G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 152,086 control chromosomes in the GnomAD database, including 5,951 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 0.27 (5951 hom., cov: 33)
• Consequence: PROX1 NM_001270616.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.835
• Publications: 2 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=-0.82).
• 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.1833+2636G>A		intron	N/A	NP_001257545.1	Q92786
	PROX1	NM_002763.5		c.1833+2636G>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.1833+2636G>A		intron	N/A	ENSP00000355925.4	Q92786
	PROX1	ENST00000435016.2	TSL:1	c.1833+2636G>A		intron	N/A	ENSP00000400694.1	Q92786
	PROX1	ENST00000881021.1		c.1833+2636G>A		intron	N/A	ENSP00000551080.1

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41679 AN: 151968 Hom.: 5939 Cov.: 33

Gnomad AFR AF: 0.268

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.389

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.277

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.281

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

GnomAD4 genome AF: 0.274 AC: 41739 AN: 152086 Hom.: 5951 Cov.: 33 AF XY: 0.276 AC XY: 20516 AN XY: 74356

African (AFR) AF: 0.268 AC: 11113 AN: 41480

American (AMR) AF: 0.390 AC: 5957 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 926 AN: 3466

East Asian (EAS) AF: 0.308 AC: 1596 AN: 5182

South Asian (SAS) AF: 0.161 AC: 775 AN: 4812

European-Finnish (FIN) AF: 0.277 AC: 2928 AN: 10570

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.259 AC: 17624 AN: 67976

Other (OTH) AF: 0.282 AC: 596 AN: 2112

Alfa AF: 0.272 Hom.: 7412

Bravo AF: 0.285

Asia WGS AF: 0.287 AC: 1000 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.9
DANN	Benign	0.43
PhyloP100		0.83
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

Other links and lift over

dbSNP: rs4655480; hg19: chr1-214181251;