rs3754140

Variant names:

• chr1-214003037-T-C
• rs3754140
• NM_001270616.2:c.1726-2128T>C

Variant summary

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

The NM_001270616.2(PROX1):​c.1726-2128T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 151,992 control chromosomes in the GnomAD database, including 6,254 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 (6254 hom., cov: 33)
• Consequence: PROX1 NM_001270616.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02
• Publications: 5 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.383 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.1726-2128T>C		intron	N/A	NP_001257545.1	Q92786
	PROX1	NM_002763.5		c.1726-2128T>C		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.1726-2128T>C		intron	N/A	ENSP00000355925.4	Q92786
	PROX1	ENST00000435016.2	TSL:1	c.1726-2128T>C		intron	N/A	ENSP00000400694.1	Q92786
	PROX1	ENST00000881021.1		c.1726-2128T>C		intron	N/A	ENSP00000551080.1

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42791 AN: 151874 Hom.: 6241 Cov.: 33

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.391

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.285

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

GnomAD4 genome AF: 0.282 AC: 42852 AN: 151992 Hom.: 6254 Cov.: 33 AF XY: 0.283 AC XY: 21060 AN XY: 74308

African (AFR) AF: 0.291 AC: 12056 AN: 41448

American (AMR) AF: 0.391 AC: 5973 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 928 AN: 3472

East Asian (EAS) AF: 0.315 AC: 1627 AN: 5166

South Asian (SAS) AF: 0.162 AC: 782 AN: 4820

European-Finnish (FIN) AF: 0.282 AC: 2973 AN: 10552

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.260 AC: 17683 AN: 67952

Other (OTH) AF: 0.286 AC: 605 AN: 2112

Alfa AF: 0.281 Hom.: 755

Bravo AF: 0.294

Asia WGS AF: 0.294 AC: 1022 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	9.2
DANN	Benign	0.68
PhyloP100		1.0
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: rs3754140; hg19: chr1-214176380;