Genetic Variant PROX1:p.Leu243Met (chr1-213997262-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001270616.2(PROX1):c.727C>A(p.Leu243Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PROX1
NM_001270616.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.13

Publications

0 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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.752

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROX1	NM_001270616.2 link	c.727C>A	p.Leu243Met	missense_variant	Exon 2 of 5	ENST00000366958.9	NP_001257545.1	Q92786

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PROX1	ENST00000366958.9 link	c.727C>A	p.Leu243Met	missense_variant	Exon 2 of 5	1	NM_001270616.2	ENSP00000355925.4	Q92786
PROX1	ENST00000435016.2 link	c.727C>A	p.Leu243Met	missense_variant	Exon 2 of 5	1		ENSP00000400694.1	Q92786
PROX1	ENST00000471129.1 link	c.*37C>A		downstream_gene_variant		3		ENSP00000419517.1	C9JU29

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461290

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726946

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44616

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26088

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86162

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111784

Other (OTH)

AF:

0.00

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 01, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.727C>A (p.L243M) alteration is located in exon 2 (coding exon 1) of the PROX1 gene. This alteration results from a C to A substitution at nucleotide position 727, causing the leucine (L) at amino acid position 243 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Uncertain

0.097

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

T;T;T;T

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

.;.;D;.

M_CAP

Benign

0.023

MetaRNN

Pathogenic

0.75

D;D;D;D

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.1

M;M;M;M

PhyloP100

6.1

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.7

N;N;N;N

REVEL

Uncertain

0.38

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.72

MutPred

0.56

Gain of methylation at K248 (P = 0.0828);Gain of methylation at K248 (P = 0.0828);Gain of methylation at K248 (P = 0.0828);Gain of methylation at K248 (P = 0.0828);

MVP

0.53

MPC

1.6

ClinPred

0.95

GERP RS

5.9

Varity_R

0.60

gMVP

0.36

Mutation Taster

=57/43

polymorphism

(source)

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

Publications

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1-213997262-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over