rs267606818
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_182925.5(FLT4):c.2569G>A(p.Gly857Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 34)
Consequence
FLT4
NM_182925.5 missense
NM_182925.5 missense
Scores
18
1
Clinical Significance
Conservation
PhyloP100: 7.90
Genes affected
FLT4 (HGNC:3767): (fms related receptor tyrosine kinase 4) This gene encodes a tyrosine kinase receptor for vascular endothelial growth factors C and D. The protein is thought to be involved in lymphangiogenesis and maintenance of the lymphatic endothelium. Mutations in this gene cause hereditary lymphedema type IA. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
?
In a binding_site (size 8) in uniprot entity VGFR3_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_182925.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.995
PP5
?
Variant 5-180619743-C-T is Pathogenic according to our data. Variant chr5-180619743-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-180619743-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLT4 | NM_182925.5 | c.2569G>A | p.Gly857Arg | missense_variant | 18/30 | ENST00000261937.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLT4 | ENST00000261937.11 | c.2569G>A | p.Gly857Arg | missense_variant | 18/30 | 1 | NM_182925.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD3 genomes
?
Cov.:
34
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 34
GnomAD4 genome
?
Cov.:
34
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary lymphedema type I Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2000 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital heart defects 7, multiple types (MIM#618780) and lymphatic malformation 1 (MIM#153100). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 23074044, 30232381). (I) 0115 - Variants in this gene are known to have variable expressivity. Variable expressivity has been reported for the lymphatic malformation phenotype (PMID: 23074044). There is also a patient reported with a recurrent frameshift variant who has both tetralogy of Fallot and lymphoedema (PMID: 30232381). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional protein tryosine kinase domain, and affects the kinase motif that is a critical part of the ATP-binding site (DECIPHER, PMID: 10835628). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been identified in four families with lymphoedema (PMIDs: 10835628, 15904433, 19002718, 24167460). (SP) 0902 - This variant has moderate evidence for segregation with disease. This variant has been shown to segregate with disease across several generations of two different families (PMIDs: 10835628, 15904433). In one of these families the variant was also identified in two unaffected individuals; however, incomplete penetrance is established for this gene. (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been shown to decrease tyrosine-kinase activity causing poor activation of downstream signalling cascades (PMID: 10835628). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 27, 2023 | Published functional studies demonstrate a damaging effect on endothelial cell differentiation and tyrosine phosphorylation (Suzuki et al., 2005); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15904433, 11553610, 10835628, 11114740, 21490960, 27177310, 23074044, 19296866, 15102829, 11427983, 15389531, 15561887) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;.
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;.;D
Vest4
MutPred
Gain of MoRF binding (P = 0.0084);Gain of MoRF binding (P = 0.0084);Gain of MoRF binding (P = 0.0084);
MVP
MPC
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