5-180612606-C-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.3437G>A(p.Arg1146His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0942 in 1,611,386 control chromosomes in the GnomAD database, including 8,199 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. R1146G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.071 ( 544 hom., cov: 32)

Exomes 𝑓: 0.097 ( 7655 hom. )

Consequence

FLT4
NM_182925.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.746

Publications

20 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=0.00330472).

BP6

Variant 5-180612606-C-T is Benign according to our data. Variant chr5-180612606-C-T is described in ClinVar as Benign. ClinVar VariationId is 263050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLT4	NM_182925.5 link	c.3437G>A	p.Arg1146His	missense_variant	Exon 26 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.3437G>A	p.Arg1146His	missense_variant	Exon 26 of 30	1	NM_182925.5	ENSP00000261937.6		P35916-2

Frequencies

GnomAD3 genomes

AF:

0.0715

AC:

10873

AN:

152046

Hom.:

544

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0192

Gnomad AMI

AF:

0.183

Gnomad AMR

AF:

0.0460

Gnomad ASJ

AF:

0.0776

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0321

Gnomad FIN

AF:

0.121

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.108

Gnomad OTH

AF:

0.0675

GnomAD2 exomes

AF:

0.0748

AC:

18772

AN:

251056

AF XY:

0.0747

show subpopulations

Gnomad AFR exome

AF:

0.0161

Gnomad AMR exome

AF:

0.0352

Gnomad ASJ exome

AF:

0.0867

Gnomad EAS exome

AF:

0.000435

Gnomad FIN exome

AF:

0.122

Gnomad NFE exome

AF:

0.108

Gnomad OTH exome

AF:

0.0783

GnomAD4 exome

AF:

0.0966

AC:

140933

AN:

1459222

Hom.:

7655

Cov.:

AF XY:

0.0947

AC XY:

68746

AN XY:

726100

show subpopulations

African (AFR)

AF:

0.0151

AC:

506

AN:

33462

American (AMR)

AF:

0.0371

AC:

1659

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0868

AC:

2266

AN:

26116

East Asian (EAS)

AF:

0.000327

AC:

AN:

39698

South Asian (SAS)

AF:

0.0364

AC:

3138

AN:

86214

European-Finnish (FIN)

AF:

0.126

AC:

6717

AN:

53382

Middle Eastern (MID)

AF:

0.0879

AC:

507

AN:

5768

European-Non Finnish (NFE)

AF:

0.109

AC:

121086

AN:

1109560

Other (OTH)

AF:

0.0836

AC:

5041

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

6001

12003

18004

24006

30007

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4292

8584

12876

17168

21460

<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:

0.0714

AC:

10869

AN:

152164

Hom.:

544

Cov.:

AF XY:

0.0689

AC XY:

5121

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.0191

AC:

794

AN:

41550

American (AMR)

AF:

0.0459

AC:

701

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0776

AC:

269

AN:

3466

East Asian (EAS)

AF:

0.000387

AC:

AN:

5174

South Asian (SAS)

AF:

0.0324

AC:

156

AN:

4820

European-Finnish (FIN)

AF:

0.121

AC:

1287

AN:

10610

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.108

AC:

7333

AN:

67942

Other (OTH)

AF:

0.0668

AC:

141

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

500

1000

1500

2000

2500

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

232

348

464

580

<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:

0.0922

Hom.:

1537

Bravo

AF:

0.0641

TwinsUK

AF:

0.111

AC:

413

ALSPAC

AF:

0.113

AC:

435

ESP6500AA

AF:

0.0216

AC:

ESP6500EA

AF:

0.100

AC:

860

ExAC

AF:

0.0755

AC:

9163

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0922

EpiControl

AF:

0.102

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1

Jun 09, 2021

GeneDx

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

0.065

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.28

T;.;T

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.59

T;T;T

MetaRNN

Benign

0.0033

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.63

N;N;.

PhyloP100

0.75

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.25

N;N;N

REVEL

Benign

0.094

Sift

Benign

0.16

T;T;T

Sift4G

Benign

0.17

T;T;T

Polyphen

0.0020

B;.;B

Vest4

0.11

MPC

0.76

ClinPred

0.0015

GERP RS

-0.63

Varity_R

0.031

gMVP

0.23

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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