chr1-213997799-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2PP3
The NM_001270616.2(PROX1):c.1264G>A(p.Asp422Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,890 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: 0.0000062 ( 0 hom. )
Consequence
PROX1
NM_001270616.2 missense
NM_001270616.2 missense
Scores
2
3
13
Clinical Significance
Conservation
PhyloP100: 10.0
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, PROX1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.747
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PROX1 | NM_001270616.2 | c.1264G>A | p.Asp422Asn | missense_variant | 2/5 | ENST00000366958.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PROX1 | ENST00000366958.9 | c.1264G>A | p.Asp422Asn | missense_variant | 2/5 | 1 | NM_001270616.2 | P1 | |
PROX1 | ENST00000435016.2 | c.1264G>A | p.Asp422Asn | missense_variant | 2/5 | 1 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461890Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727246
GnomAD4 exome
AF:
AC:
9
AN:
1461890
Hom.:
Cov.:
31
AF XY:
AC XY:
4
AN XY:
727246
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
Alfa
AF:
Hom.:
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 | Oct 26, 2022 | The c.1264G>A (p.D422N) alteration is located in exon 2 (coding exon 1) of the PROX1 gene. This alteration results from a G to A substitution at nucleotide position 1264, causing the aspartic acid (D) at amino acid position 422 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;T;T;T
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
T
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;L;L
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N
REVEL
Benign
Sift
Benign
T;T;T;T
Sift4G
Benign
T;T;T;T
Polyphen
B;B;B;B
Vest4
MutPred
Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP
MPC
0.69
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at