rs35874891

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.1580A>G(p.Asn527Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00445 in 1,613,484 control chromosomes in the GnomAD database, including 292 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. N527D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.023 ( 139 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 153 hom. )

Consequence

FLT4
NM_182925.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.13

Publications

8 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=0.0020684302).

BP6

Variant 5-180622808-T-C is Benign according to our data. Variant chr5-180622808-T-C is described in ClinVar as Benign. ClinVar VariationId is 263029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLT4	NM_182925.5 link	c.1580A>G	p.Asn527Ser	missense_variant	Exon 12 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.1580A>G	p.Asn527Ser	missense_variant	Exon 12 of 30	1	NM_182925.5	ENSP00000261937.6		P35916-2

Frequencies

GnomAD3 genomes

AF:

0.0234

AC:

3554

AN:

152102

Hom.:

139

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0816

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00760

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000368

Gnomad OTH

AF:

0.0163

GnomAD2 exomes

AF:

0.00591

AC:

1482

AN:

250658

AF XY:

0.00438

show subpopulations

Gnomad AFR exome

AF:

0.0822

Gnomad AMR exome

AF:

0.00289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000203

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00248

AC:

3619

AN:

1461264

Hom.:

153

Cov.:

AF XY:

0.00215

AC XY:

1562

AN XY:

726916

show subpopulations

African (AFR)

AF:

0.0888

AC:

2971

AN:

33452

American (AMR)

AF:

0.00367

AC:

164

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000267

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53032

Middle Eastern (MID)

AF:

0.00382

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000980

AC:

109

AN:

1111822

Other (OTH)

AF:

0.00547

AC:

330

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

181

362

542

723

904

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

276

368

460

<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:

0.0234

AC:

3564

AN:

152220

Hom.:

139

Cov.:

AF XY:

0.0228

AC XY:

1694

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0816

AC:

3387

AN:

41514

American (AMR)

AF:

0.00759

AC:

116

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000368

AC:

AN:

68008

Other (OTH)

AF:

0.0161

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

170

340

511

681

851

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0107

Hom.:

Bravo

AF:

0.0271

ESP6500AA

AF:

0.0817

AC:

360

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00733

AC:

890

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 06, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

0.077

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;.;T

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.067

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.93

D;D;D

MetaRNN

Benign

0.0021

T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.5

L;L;.

PhyloP100

3.1

PrimateAI

Benign

0.38

PROVEAN

Benign

-2.0

N;N;N

REVEL

Benign

0.26

Sift

Benign

0.22

T;T;T

Sift4G

Benign

0.73

T;T;T

Polyphen

0.12

B;.;B

Vest4

0.23

MVP

0.37

MPC

0.81

ClinPred

0.029

GERP RS

4.2

Varity_R

0.23

gMVP

0.21

Mutation Taster

=90/10

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

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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