rs201796032

Variant names:

Variant summary

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

The NM_182925.5(FLT4):c.4006G>A(p.Glu1336Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00109 in 1,614,094 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00097 ( 18 hom. )

Consequence

FLT4
NM_182925.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.96

Publications

11 publications found

Variant links:

COSMIC-nc: COSV56123171

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=0.0079502165).

BP6

Variant 5-180603278-C-T is Benign according to our data. Variant chr5-180603278-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1330670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00229 (349/152380) while in subpopulation EAS AF = 0.00694 (36/5184). AF 95% confidence interval is 0.00516. There are 4 homozygotes in GnomAd4. There are 267 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 349 AD gene.

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.4006G>A	p.Glu1336Lys	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.4006G>A	p.Glu1336Lys	missense	Exon 30 of 30	ENSP00000261937.6	P35916-2
FLT4	ENST00000955857.1		c.4282G>A	p.Glu1428Lys	missense	Exon 30 of 30	ENSP00000625916.1
FLT4	ENST00000861588.1		c.4072G>A	p.Glu1358Lys	missense	Exon 30 of 30	ENSP00000531647.1

Frequencies

GnomAD3 genomes

AF:

0.00229

AC:

349

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00693

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0247

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000367

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00252

AC:

628

AN:

248992

AF XY:

0.00256

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000435

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00605

Gnomad FIN exome

AF:

0.0203

Gnomad NFE exome

AF:

0.000474

Gnomad OTH exome

AF:

0.00181

GnomAD4 exome

AF:

0.000968

AC:

1415

AN:

1461714

Hom.:

Cov.:

AF XY:

0.000946

AC XY:

688

AN XY:

727150

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000581

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26126

East Asian (EAS)

AF:

0.00479

AC:

190

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.0183

AC:

979

AN:

53360

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000137

AC:

152

AN:

1111984

Other (OTH)

AF:

0.00101

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

170

256

341

426

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.00229

AC:

349

AN:

152380

Hom.:

Cov.:

AF XY:

0.00358

AC XY:

267

AN XY:

74520

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41590

American (AMR)

AF:

0.00137

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00694

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0247

AC:

262

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000367

AC:

AN:

68040

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000502

Hom.:

Bravo

AF:

0.000695

ExAC

AF:

0.00205

AC:

249

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.26

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0080

MetaSVM

Uncertain

0.080

MutationAssessor

Uncertain

2.7

PhyloP100

5.0

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.52

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.015

Polyphen

1.0

Vest4

0.23

MVP

0.31

MPC

0.21

ClinPred

0.065

GERP RS

3.8

Varity_R

0.38

gMVP

0.60

Mutation Taster

=66/34

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

Computational scores

Splicing

Publications

Other links and lift over