rs448012

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.2670C>G(p.His890Gln) variant causes a missense change. The variant allele was found at a frequency of 0.628 in 1,609,192 control chromosomes in the GnomAD database, including 319,683 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.61 ( 28934 hom., cov: 32)

Exomes 𝑓: 0.63 ( 290749 hom. )

Consequence

FLT4
NM_182925.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.68

Publications

56 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):

lymphatic malformation 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
capillary infantile hemangioma
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
congenital heart defects, multiple types, 7
Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
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=1.3976962E-6).

BP6

Variant 5-180619344-G-C is Benign according to our data. Variant chr5-180619344-G-C is described in ClinVar as Benign. ClinVar VariationId is 263039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLT4	NM_182925.5 link	c.2670C>G	p.His890Gln	missense_variant	Exon 19 of 30	ENST00000261937.11	NP_891555.2	P35916-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLT4	ENST00000261937.11 link	c.2670C>G	p.His890Gln	missense_variant	Exon 19 of 30	1	NM_182925.5	ENSP00000261937.6		P35916-2

Frequencies

GnomAD3 genomes

AF:

0.612

AC:

92873

AN:

151658

Hom.:

28920

Cov.:

show subpopulations

Gnomad AFR

AF:

0.543

Gnomad AMI

AF:

0.697

Gnomad AMR

AF:

0.697

Gnomad ASJ

AF:

0.568

Gnomad EAS

AF:

0.494

Gnomad SAS

AF:

0.578

Gnomad FIN

AF:

0.704

Gnomad MID

AF:

0.600

Gnomad NFE

AF:

0.634

Gnomad OTH

AF:

0.624

GnomAD2 exomes

AF:

0.630

AC:

153516

AN:

243662

AF XY:

0.623

show subpopulations

Gnomad AFR exome

AF:

0.543

Gnomad AMR exome

AF:

0.755

Gnomad ASJ exome

AF:

0.571

Gnomad EAS exome

AF:

0.488

Gnomad FIN exome

AF:

0.704

Gnomad NFE exome

AF:

0.636

Gnomad OTH exome

AF:

0.628

GnomAD4 exome

AF:

0.630

AC:

917892

AN:

1457416

Hom.:

290749

Cov.:

AF XY:

0.627

AC XY:

455002

AN XY:

725184

show subpopulations

African (AFR)

AF:

0.537

AC:

17972

AN:

33440

American (AMR)

AF:

0.749

AC:

33420

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.580

AC:

15132

AN:

26086

East Asian (EAS)

AF:

0.494

AC:

19574

AN:

39660

South Asian (SAS)

AF:

0.569

AC:

49028

AN:

86208

European-Finnish (FIN)

AF:

0.705

AC:

35674

AN:

50632

Middle Eastern (MID)

AF:

0.581

AC:

3335

AN:

5744

European-Non Finnish (NFE)

AF:

0.636

AC:

706591

AN:

1110720

Other (OTH)

AF:

0.617

AC:

37166

AN:

60284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

15857

31714

47570

63427

79284

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18688

37376

56064

74752

93440

<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:

0.612

AC:

92924

AN:

151776

Hom.:

28934

Cov.:

AF XY:

0.616

AC XY:

45667

AN XY:

74170

show subpopulations

African (AFR)

AF:

0.542

AC:

22459

AN:

41404

American (AMR)

AF:

0.697

AC:

10647

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.568

AC:

1966

AN:

3464

East Asian (EAS)

AF:

0.493

AC:

2504

AN:

5080

South Asian (SAS)

AF:

0.578

AC:

2794

AN:

4832

European-Finnish (FIN)

AF:

0.704

AC:

7425

AN:

10540

Middle Eastern (MID)

AF:

0.601

AC:

173

AN:

288

European-Non Finnish (NFE)

AF:

0.634

AC:

43022

AN:

67878

Other (OTH)

AF:

0.619

AC:

1304

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1806

3611

5417

7222

9028

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

758

1516

2274

3032

3790

<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:

0.625

Hom.:

9730

Bravo

AF:

0.608

TwinsUK

AF:

0.646

AC:

2394

ALSPAC

AF:

0.643

AC:

2479

ESP6500AA

AF:

0.545

AC:

2398

ESP6500EA

AF:

0.623

AC:

5356

ExAC

AF:

0.621

AC:

74755

Asia WGS

AF:

0.544

AC:

1889

AN:

3478

EpiCase

AF:

0.627

EpiControl

AF:

0.624

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 62% of total chromosomes in ExAC -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Congenital heart defects, multiple types, 7

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Nov 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary lymphedema type I

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.61

D;.;T

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.31

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.75

T;T;T

MetaRNN

Benign

0.0000014

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.040

N;N;.

PhyloP100

3.7

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-5.1

D;D;D

REVEL

Uncertain

0.31

Sift

Benign

0.045

D;D;D

Sift4G

Uncertain

0.033

D;D;D

Polyphen

0.18

B;.;B

Vest4

0.39

MutPred

0.19

Gain of catalytic residue at H890 (P = 0.0859);Gain of catalytic residue at H890 (P = 0.0859);Gain of catalytic residue at H890 (P = 0.0859);

MPC

1.2

ClinPred

0.050

GERP RS

1.2

PromoterAI

0.039

Neutral

(source)

Varity_R

0.50

gMVP

0.77

Mutation Taster

=91/9

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over