rs121909656

Positions:

• chr5-180614083-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The ENST00000261937.11(FLT4):​c.3316G>A​(p.Glu1106Lys) 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. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1106D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: FLT4 ENST00000261937.11 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.89

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-180614081-C-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 5-180614083-C-T is Pathogenic according to our data. Variant chr5-180614083-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-180614083-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLT4	NM_182925.5	c.3316G>A	p.Glu1106Lys	missense_variant	24/30	ENST00000261937.11	NP_891555.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLT4	ENST00000261937.11	c.3316G>A	p.Glu1106Lys	missense_variant	24/30	1	NM_182925.5	ENSP00000261937	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hereditary lymphedema type I Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.;D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.017	D;D;D
Sift4G	Uncertain	0.027	D;D;D
Polyphen		0.66	P;.;B
Vest4		0.97
MutPred		0.95		Gain of methylation at E1106 (P = 0.0058);Gain of methylation at E1106 (P = 0.0058);Gain of methylation at E1106 (P = 0.0058);
MVP		0.96
MPC		1.2
ClinPred		0.98	D
GERP RS		2.9
Varity_R		0.83
gMVP		1.0

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

LitVar

Other links and lift over

dbSNP: rs121909656; hg19: chr5-180041083; COSMIC: COSV105855204; COSMIC: COSV105855204;