rs121909655

Variant names:

• chr5-180614142-A-G
• rs121909655
• NM_182925.5:c.3257T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_182925.5(FLT4):​c.3257T>C​(p.Ile1086Thr) 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 Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: FLT4 NM_182925.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 9.23

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 5-180614142-A-G is Pathogenic according to our data. Variant chr5-180614142-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16266.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-180614142-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLT4	NM_182925.5	c.3257T>C	p.Ile1086Thr	missense_variant	Exon 24 of 30	ENST00000261937.11	NP_891555.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLT4	ENST00000261937.11	c.3257T>C	p.Ile1086Thr	missense_variant	Exon 24 of 30	1	NM_182925.5	ENSP00000261937.6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

FLT4-related disorder Pathogenic:1

Sep 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FLT4 c.3257T>C variant is predicted to result in the amino acid substitution p.Ile1086Thr. This variant has been reported in an individual with primary lymphedema (Ghalamkarpour et al. 2006. PubMed ID: 16965327) and has been confirmed de novo in an individual who underwent lymphedema panel testing at PreventionGenetics (internal data). This variant has not been reported in the gnomAD database, indicating this variant is rare. Taken together, this variant is interpreted as likely pathogenic. -

Hereditary lymphedema type I Pathogenic:1

Oct 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.;D;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.1	M;M;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.3	D;D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;.
Polyphen		0.97	D;.;P;.
Vest4		0.92
MutPred		0.92		Gain of phosphorylation at I1086 (P = 0.021);Gain of phosphorylation at I1086 (P = 0.021);Gain of phosphorylation at I1086 (P = 0.021);.;
MVP		0.95
MPC		1.6
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.86
gMVP		0.93

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: rs121909655; hg19: chr5-180041142;