rs267606818

Positions:

• chr5-180619743-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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]

ACMG classification

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

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;.;D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	1.0	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.9	D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.97
MutPred		0.99		Gain of MoRF binding (P = 0.0084);Gain of MoRF binding (P = 0.0084);Gain of MoRF binding (P = 0.0084);
MVP		0.97
MPC		1.7
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.89
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs267606818; hg19: chr5-180046743;