Genetic Variant PROX1:c.-68+1243C>T (chr1-213989726-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001270616.2(PROX1):c.-68+1243C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 152,092 control chromosomes in the GnomAD database, including 17,315 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 0.47 ( 17273 hom., cov: 29)

Exomes 𝑓: 0.49 ( 42 hom. )

Consequence

PROX1
NM_001270616.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0600

Publications

8 publications found

Variant links:

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

PROX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.595 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.-68+1243C>T		intron	N/A	NP_001257545.1	Q92786
	PROX1	NM_002763.5		c.-68+1005C>T		intron	N/A	NP_002754.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PROX1	ENST00000366958.9	TSL:1 MANE Select	c.-68+1243C>T	intron	N/A	ENSP00000355925.4	Q92786
PROX1	ENST00000435016.2	TSL:1	c.-68+1005C>T	intron	N/A	ENSP00000400694.1	Q92786
PROX1	ENST00000881027.1		c.-84C>T	5_prime_UTR	Exon 1 of 5	ENSP00000551086.1

Frequencies

GnomAD3 genomes

AF:

0.469

AC:

71185

AN:

151664

Hom.:

17269

Cov.:

show subpopulations

Gnomad AFR

AF:

0.337

Gnomad AMI

AF:

0.635

Gnomad AMR

AF:

0.502

Gnomad ASJ

AF:

0.484

Gnomad EAS

AF:

0.612

Gnomad SAS

AF:

0.586

Gnomad FIN

AF:

0.439

Gnomad MID

AF:

0.437

Gnomad NFE

AF:

0.525

Gnomad OTH

AF:

0.469

GnomAD4 exome

AF:

0.487

AC:

151

AN:

310

Hom.:

Cov.:

AF XY:

0.482

AC XY:

109

AN XY:

226

show subpopulations

African (AFR)

AF:

0.300

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.500

AC:

AN:

South Asian (SAS)

AF:

0.250

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.504

AC:

129

AN:

256

Other (OTH)

AF:

0.429

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.469

AC:

71207

AN:

151782

Hom.:

17273

Cov.:

AF XY:

0.466

AC XY:

34565

AN XY:

74162

show subpopulations

African (AFR)

AF:

0.337

AC:

13924

AN:

41378

American (AMR)

AF:

0.502

AC:

7671

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.484

AC:

1677

AN:

3462

East Asian (EAS)

AF:

0.613

AC:

3134

AN:

5116

South Asian (SAS)

AF:

0.586

AC:

2808

AN:

4788

European-Finnish (FIN)

AF:

0.439

AC:

4633

AN:

10550

Middle Eastern (MID)

AF:

0.439

AC:

129

AN:

294

European-Non Finnish (NFE)

AF:

0.525

AC:

35671

AN:

67902

Other (OTH)

AF:

0.464

AC:

981

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1856

3711

5567

7422

9278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

676

1352

2028

2704

3380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.493

Hom.:

3740

Bravo

AF:

0.468

Asia WGS

AF:

0.566

AC:

1969

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

9.5

(source)

DANN

Benign

0.72

PhyloP100

-0.060

PromoterAI

0.0017

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over