5-180603322-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000261937.11(FLT4):c.3962G>A(p.Arg1321Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,612,680 control chromosomes in the GnomAD database, including 192 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1321W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0093 ( 14 hom., cov: 33)

Exomes 𝑓: 0.015 ( 178 hom. )

Consequence

FLT4
ENST00000261937.11 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.776

Publications

11 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=0.0055611134).

BP6

Variant 5-180603322-C-T is Benign according to our data. Variant chr5-180603322-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00927 (1412/152360) while in subpopulation NFE AF = 0.0163 (1108/68020). AF 95% confidence interval is 0.0155. There are 14 homozygotes in GnomAd4. There are 639 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1412 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000261937.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT4	NM_182925.5	MANE Select	c.3962G>A	p.Arg1321Gln	missense	Exon 30 of 30	NP_891555.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT4	ENST00000261937.11	TSL:1 MANE Select	c.3962G>A	p.Arg1321Gln	missense	Exon 30 of 30	ENSP00000261937.6
	FLT4	ENST00000502603.5	TSL:2	n.662G>A		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes

AF:

0.00929

AC:

1414

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00282

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00556

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.00602

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0163

Gnomad OTH

AF:

0.00718

GnomAD2 exomes

AF:

0.00891

AC:

2201

AN:

247058

AF XY:

0.00876

show subpopulations

Gnomad AFR exome

AF:

0.00233

Gnomad AMR exome

AF:

0.00587

Gnomad ASJ exome

AF:

0.000698

Gnomad EAS exome

AF:

0.0000546

Gnomad FIN exome

AF:

0.00777

Gnomad NFE exome

AF:

0.0149

Gnomad OTH exome

AF:

0.00990

GnomAD4 exome

AF:

0.0146

AC:

21327

AN:

1460320

Hom.:

178

Cov.:

AF XY:

0.0142

AC XY:

10333

AN XY:

726496

show subpopulations

African (AFR)

AF:

0.00203

AC:

AN:

33464

American (AMR)

AF:

0.00604

AC:

270

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.000842

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00287

AC:

247

AN:

86150

European-Finnish (FIN)

AF:

0.00852

AC:

454

AN:

53310

Middle Eastern (MID)

AF:

0.00278

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.0176

AC:

19568

AN:

1110818

Other (OTH)

AF:

0.0113

AC:

682

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1257

2515

3772

5030

6287

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

738

1476

2214

2952

3690

<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:

0.00927

AC:

1412

AN:

152360

Hom.:

Cov.:

AF XY:

0.00858

AC XY:

639

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00281

AC:

117

AN:

41594

American (AMR)

AF:

0.00555

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00393

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00602

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0163

AC:

1108

AN:

68020

Other (OTH)

AF:

0.00710

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

160

240

320

400

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0123

Hom.:

Bravo

AF:

0.00920

TwinsUK

AF:

0.0191

AC:

ALSPAC

AF:

0.0192

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0164

AC:

141

ExAC

AF:

0.00956

AC:

1160

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.52

CADD

Benign

7.1

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.086

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.072

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0056

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PhyloP100

0.78

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.36

REVEL

Benign

0.080

Sift

Benign

0.19

Sift4G

Benign

0.63

Polyphen

0.0010

Vest4

0.11

MVP

0.093

MPC

0.13

ClinPred

0.0062

GERP RS

1.4

Varity_R

0.027

gMVP

0.25

Mutation Taster

=97/3

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over