14-74855277-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001243007.2(PROX2):c.1634C>T(p.Ala545Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,404,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

PROX2
NM_001243007.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

PROX2 (HGNC:26715): (prospero homeobox 2) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

PROX2 links:

YLPM1 (HGNC:17798): (YLP motif containing 1) Enables RNA binding activity. Predicted to be involved in regulation of telomere maintenance. Predicted to act upstream of or within negative regulation of transcription by RNA polymerase II. Located in cytosol and nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

YLPM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.37845567).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROX2	NM_001243007.2 linkuse as main transcript	c.1634C>T	p.Ala545Val	missense_variant	6/6	ENST00000556489.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROX2	ENST00000556489.4 linkuse as main transcript	c.1634C>T	p.Ala545Val	missense_variant	6/6	1	NM_001243007.2	P1
PROX2	ENST00000673765.1 linkuse as main transcript	c.953C>T	p.Ala318Val	missense_variant	5/5				Q3B8N5-2
YLPM1	ENST00000554107.2 linkuse as main transcript	c.268G>A	p.Ala90Thr	missense_variant	4/4	3
YLPM1	ENST00000553381.1 linkuse as main transcript	n.298G>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000426

AC:

AN:

234944

Hom.:

AF XY:

0.00000785

AC XY:

AN XY:

127380

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000928

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1404890

Hom.:

Cov.:

AF XY:

0.0000130

AC XY:

AN XY:

691484

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000205

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2024

The c.953C>T (p.A318V) alteration is located in exon 3 (coding exon 3) of the PROX2 gene. This alteration results from a C to T substitution at nucleotide position 953, causing the alanine (A) at amino acid position 318 to be replaced by a valine (V). 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

Benign

0.27

BayesDel_addAF

Benign

-0.033

BayesDel_noAF

Benign

-0.28

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.38

T;T

MetaSVM

Benign

-0.82

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.9

D;D

Sift

Benign

0.38

T;D

Sift4G

Benign

0.18

T;D

Polyphen

0.33

B;D

Vest4

0.63

MutPred

0.34

.;Gain of catalytic residue at A545 (P = 0.1173);

MVP

0.25

MPC

0.049

ClinPred

0.68

GERP RS

5.2

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over