Genetic Variant NM_182925.5:c.3341C>T (chr5-180613101-G-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_182925.5(FLT4):c.3341C>T(p.Pro1114Leu) 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 (★).

Frequency

Genomes: not found (cov: 32)

Consequence

FLT4
NM_182925.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.98

Publications

9 publications found

Variant links:

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]

FLT4 Gene-Disease associations (from GenCC):

congenital heart defects, multiple types, 7
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
lymphatic malformation 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
capillary infantile hemangioma
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
lymphatic malformation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
tetralogy of fallot
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

FLT4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.995

PP5

Variant 5-180613101-G-A is Pathogenic according to our data. Variant chr5-180613101-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 16262.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182925.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLT4	NM_182925.5	MANE Select	c.3341C>T	p.Pro1114Leu	missense	Exon 25 of 30	NP_891555.2	P35916-2
FLT4	NM_001354989.2		c.3341C>T	p.Pro1114Leu	missense	Exon 25 of 30	NP_001341918.1	E9PD35
FLT4	NM_002020.5		c.3341C>T	p.Pro1114Leu	missense	Exon 25 of 30	NP_002011.2	P35916-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLT4	ENST00000261937.11	TSL:1 MANE Select	c.3341C>T	p.Pro1114Leu	missense	Exon 25 of 30	ENSP00000261937.6	P35916-2
FLT4	ENST00000502649.5	TSL:1	c.3341C>T	p.Pro1114Leu	missense	Exon 25 of 30	ENSP00000426057.1	E9PD35
FLT4	ENST00000393347.7	TSL:1	c.3341C>T	p.Pro1114Leu	missense	Exon 25 of 30	ENSP00000377016.3	P35916-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary lymphedema type I (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.81

MutationAssessor

Uncertain

2.1

PhyloP100

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-8.8

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.95

MutPred

0.97

Loss of disorder (P = 0.1742)

MVP

0.96

MPC

1.6

ClinPred

0.99

GERP RS

3.9

Varity_R

0.85

gMVP

0.97

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over