NM_182925.5:c.3971G>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_182925.5(FLT4):c.3971G>T(p.Arg1324Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0968 in 1,613,696 control chromosomes in the GnomAD database, including 8,130 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1324P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.081 ( 567 hom., cov: 33)

Exomes 𝑓: 0.099 ( 7563 hom. )

Consequence

FLT4
NM_182925.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.34

Publications

49 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015855432).

BP6

Variant 5-180603313-C-A is Benign according to our data. Variant chr5-180603313-C-A is described in ClinVar as Benign. ClinVar VariationId is 263057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT4	NM_182925.5	MANE Select	c.3971G>T	p.Arg1324Leu	missense	Exon 30 of 30	NP_891555.2	P35916-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLT4	ENST00000261937.11	TSL:1 MANE Select	c.3971G>T	p.Arg1324Leu	missense	Exon 30 of 30	ENSP00000261937.6	P35916-2
FLT4	ENST00000955857.1		c.4247G>T	p.Arg1416Leu	missense	Exon 30 of 30	ENSP00000625916.1
FLT4	ENST00000861588.1		c.4037G>T	p.Arg1346Leu	missense	Exon 30 of 30	ENSP00000531647.1

Frequencies

GnomAD3 genomes

AF:

0.0806

AC:

12274

AN:

152246

Hom.:

567

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0512

Gnomad AMI

AF:

0.297

Gnomad AMR

AF:

0.0613

Gnomad ASJ

AF:

0.111

Gnomad EAS

AF:

0.000576

Gnomad SAS

AF:

0.0409

Gnomad FIN

AF:

0.0860

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.107

Gnomad OTH

AF:

0.0755

GnomAD2 exomes

AF:

0.0786

AC:

19397

AN:

246898

AF XY:

0.0794

show subpopulations

Gnomad AFR exome

AF:

0.0535

Gnomad AMR exome

AF:

0.0448

Gnomad ASJ exome

AF:

0.0986

Gnomad EAS exome

AF:

0.000656

Gnomad FIN exome

AF:

0.0940

Gnomad NFE exome

AF:

0.110

Gnomad OTH exome

AF:

0.0845

GnomAD4 exome

AF:

0.0985

AC:

143954

AN:

1461332

Hom.:

7563

Cov.:

AF XY:

0.0968

AC XY:

70361

AN XY:

726924

show subpopulations

African (AFR)

AF:

0.0525

AC:

1759

AN:

33474

American (AMR)

AF:

0.0471

AC:

2104

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.101

AC:

2638

AN:

26112

East Asian (EAS)

AF:

0.000353

AC:

AN:

39684

South Asian (SAS)

AF:

0.0465

AC:

4006

AN:

86194

European-Finnish (FIN)

AF:

0.0925

AC:

4934

AN:

53314

Middle Eastern (MID)

AF:

0.0644

AC:

370

AN:

5748

European-Non Finnish (NFE)

AF:

0.110

AC:

122806

AN:

1111770

Other (OTH)

AF:

0.0882

AC:

5323

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

7629

15258

22888

30517

38146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4388

8776

13164

17552

21940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0806

AC:

12283

AN:

152364

Hom.:

567

Cov.:

AF XY:

0.0790

AC XY:

5889

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.0513

AC:

2135

AN:

41586

American (AMR)

AF:

0.0612

AC:

936

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.111

AC:

386

AN:

3472

East Asian (EAS)

AF:

0.000578

AC:

AN:

5192

South Asian (SAS)

AF:

0.0408

AC:

197

AN:

4832

European-Finnish (FIN)

AF:

0.0860

AC:

914

AN:

10624

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.107

AC:

7258

AN:

68032

Other (OTH)

AF:

0.0747

AC:

158

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

601

1203

1804

2406

3007

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

256

384

512

640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0952

Hom.:

1219

Bravo

AF:

0.0794

TwinsUK

AF:

0.119

AC:

442

ALSPAC

AF:

0.107

AC:

413

ESP6500AA

AF:

0.0522

AC:

230

ESP6500EA

AF:

0.109

AC:

934

ExAC

AF:

0.0803

AC:

9752

EpiCase

AF:

0.111

EpiControl

AF:

0.108

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.0060

(source)

DANN

Benign

0.39

DEOGEN2

Benign

0.078

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.20

PhyloP100

-1.3

PrimateAI

Benign

0.24

PROVEAN

Benign

0.12

REVEL

Benign

0.068

Sift

Benign

0.65

Sift4G

Benign

0.66

Polyphen

0.0

Vest4

0.023

MPC

0.14

ClinPred

0.00030

GERP RS

-8.8

Varity_R

0.029

gMVP

0.13

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over