dbSNP rs34255532: FLT4:p.Pro954Ser (chr5-180618911-G-A) – ACMG Classification: Benign (-20 pts)

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.2860C>T(p.Pro954Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0057 in 1,585,876 control chromosomes in the GnomAD database, including 36 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 0.0035 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0059 ( 32 hom. )

Consequence

FLT4
NM_182925.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:7

Conservation

PhyloP100: 3.79

Publications

22 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=0.006272793).

BP6

Variant 5-180618911-G-A is Benign according to our data. Variant chr5-180618911-G-A is described in ClinVar as Benign. ClinVar VariationId is 16264.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 = 0.00346 (527/152298) while in subpopulation NFE AF = 0.00619 (421/68010). AF 95% confidence interval is 0.0057. There are 4 homozygotes in GnomAd4. There are 225 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 527 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FLT4	NM_182925.5	MANE Select	c.2860C>T	p.Pro954Ser	missense	Exon 21 of 30	NP_891555.2
FLT4	NM_001354989.2		c.2860C>T	p.Pro954Ser	missense	Exon 21 of 30	NP_001341918.1
FLT4	NM_002020.5		c.2860C>T	p.Pro954Ser	missense	Exon 21 of 30	NP_002011.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FLT4	ENST00000261937.11	TSL:1 MANE Select	c.2860C>T	p.Pro954Ser	missense	Exon 21 of 30	ENSP00000261937.6
FLT4	ENST00000502649.5	TSL:1	c.2860C>T	p.Pro954Ser	missense	Exon 21 of 30	ENSP00000426057.1
FLT4	ENST00000393347.7	TSL:1	c.2860C>T	p.Pro954Ser	missense	Exon 21 of 30	ENSP00000377016.3

Frequencies

GnomAD3 genomes

AF:

0.00346

AC:

527

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00619

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00354

AC:

681

AN:

192522

AF XY:

0.00372

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00148

Gnomad ASJ exome

AF:

0.000228

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000472

Gnomad NFE exome

AF:

0.00600

Gnomad OTH exome

AF:

0.00422

GnomAD4 exome

AF:

0.00594

AC:

8519

AN:

1433578

Hom.:

Cov.:

AF XY:

0.00597

AC XY:

4242

AN XY:

710598

show subpopulations

African (AFR)

AF:

0.00115

AC:

AN:

33134

American (AMR)

AF:

0.00166

AC:

AN:

40938

Ashkenazi Jewish (ASJ)

AF:

0.000157

AC:

AN:

25528

East Asian (EAS)

AF:

0.00

AC:

AN:

38434

South Asian (SAS)

AF:

0.00368

AC:

304

AN:

82508

European-Finnish (FIN)

AF:

0.000632

AC:

AN:

49072

Middle Eastern (MID)

AF:

0.00510

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.00699

AC:

7679

AN:

1099036

Other (OTH)

AF:

0.00618

AC:

366

AN:

59242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

513

1026

1540

2053

2566

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

296

592

888

1184

1480

<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:

0.00346

AC:

527

AN:

152298

Hom.:

Cov.:

AF XY:

0.00302

AC XY:

225

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

41582

American (AMR)

AF:

0.00216

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00228

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00619

AC:

421

AN:

68010

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

122

152

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:

0.00502

Hom.:

Bravo

AF:

0.00354

ESP6500AA

AF:

0.00163

AC:

ESP6500EA

AF:

0.00496

AC:

ExAC

AF:

0.00307

AC:

362

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Capillary infantile hemangioma (1)

Colorectal cancer (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.40

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0063

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.80

PhyloP100

3.8

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.3

REVEL

Benign

0.16

Sift

Benign

0.088

Sift4G

Benign

0.18

Polyphen

0.016

Vest4

0.23

MVP

0.41

MPC

0.78

ClinPred

0.011

GERP RS

4.0

PromoterAI

0.016

Neutral

(source)

Varity_R

0.15

gMVP

0.61

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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