5-180630293-T-C

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.445A>G(p.Asn149Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.092 in 1,612,212 control chromosomes in the GnomAD database, including 7,695 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.070 ( 525 hom., cov: 32)

Exomes 𝑓: 0.094 ( 7170 hom. )

Consequence

FLT4
NM_182925.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.40

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=0.0018151104).

BP6

Variant 5-180630293-T-C is Benign according to our data. Variant chr5-180630293-T-C is described in ClinVar as [Benign]. Clinvar id is 263062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLT4	NM_182925.5 link	c.445A>G	p.Asn149Asp	missense_variant	Exon 4 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.445A>G	p.Asn149Asp	missense_variant	Exon 4 of 30	1	NM_182925.5	ENSP00000261937.6		P35916-2

Frequencies

GnomAD3 genomes

AF:

0.0704

AC:

10715

AN:

152134

Hom.:

525

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0191

Gnomad AMI

AF:

0.150

Gnomad AMR

AF:

0.0500

Gnomad ASJ

AF:

0.0625

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0414

Gnomad FIN

AF:

0.118

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.106

Gnomad OTH

AF:

0.0699

GnomAD2 exomes

AF:

0.0738

AC:

18397

AN:

249392

AF XY:

0.0745

show subpopulations

Gnomad AFR exome

AF:

0.0174

Gnomad AMR exome

AF:

0.0373

Gnomad ASJ exome

AF:

0.0673

Gnomad EAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.116

Gnomad NFE exome

AF:

0.105

Gnomad OTH exome

AF:

0.0751

GnomAD4 exome

AF:

0.0943

AC:

137692

AN:

1459960

Hom.:

7170

Cov.:

AF XY:

0.0928

AC XY:

67414

AN XY:

726352

show subpopulations

African (AFR)

AF:

0.0152

AC:

509

AN:

33480

American (AMR)

AF:

0.0390

AC:

1744

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0665

AC:

1738

AN:

26130

East Asian (EAS)

AF:

0.000277

AC:

AN:

39700

South Asian (SAS)

AF:

0.0466

AC:

4017

AN:

86256

European-Finnish (FIN)

AF:

0.119

AC:

6163

AN:

51734

Middle Eastern (MID)

AF:

0.0877

AC:

506

AN:

5768

European-Non Finnish (NFE)

AF:

0.106

AC:

118097

AN:

1111810

Other (OTH)

AF:

0.0813

AC:

4907

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

7315

14631

21946

29262

36577

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0704

AC:

10712

AN:

152252

Hom.:

525

Cov.:

AF XY:

0.0683

AC XY:

5087

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0190

AC:

791

AN:

41560

American (AMR)

AF:

0.0498

AC:

762

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0625

AC:

217

AN:

3472

East Asian (EAS)

AF:

0.000579

AC:

AN:

5180

South Asian (SAS)

AF:

0.0417

AC:

201

AN:

4824

European-Finnish (FIN)

AF:

0.118

AC:

1254

AN:

10610

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.106

AC:

7184

AN:

68002

Other (OTH)

AF:

0.0687

AC:

145

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

504

1007

1511

2014

2518

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0794

Hom.:

523

Bravo

AF:

0.0632

TwinsUK

AF:

0.104

AC:

385

ALSPAC

AF:

0.108

AC:

415

ESP6500AA

AF:

0.0218

AC:

ESP6500EA

AF:

0.0975

AC:

838

ExAC

AF:

0.0747

AC:

9037

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.0937

EpiControl

AF:

0.101

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

0.097

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.21

T;.;T;T

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.39

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.63

T;T;T;T

MetaRNN

Benign

0.0018

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;N;.;.

PhyloP100

2.4

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.0

N;N;N;.

REVEL

Benign

0.064

Sift

Benign

0.19

T;T;T;.

Sift4G

Benign

0.21

T;T;T;T

Polyphen

0.0

B;.;B;B

Vest4

0.061

MPC

0.68

ClinPred

0.0043

GERP RS

3.0

Varity_R

0.14

gMVP

0.65

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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5-180630293-T-C

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