Genetic Variant FLT4:c.1258+14G>A (chr5-180626097-C-T) – ACMG Classification: Benign (-20 pts)

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.1258+14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0408 in 1,612,718 control chromosomes in the GnomAD database, including 1,999 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.044 ( 210 hom., cov: 33)

Exomes 𝑓: 0.040 ( 1789 hom. )

Consequence

FLT4
NM_182925.5 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.277

Publications

7 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):

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 (BayesDel_noAF=-0.88).

BP6

Variant 5-180626097-C-T is Benign according to our data. Variant chr5-180626097-C-T is described in ClinVar as Benign. ClinVar VariationId is 263021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

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	Effect	Exon Rank	Protein	UniProt
FLT4	NM_182925.5	MANE Select	c.1258+14G>A	intron	N/A	NP_891555.2	P35916-2
FLT4	NM_001354989.2		c.1258+14G>A	intron	N/A	NP_001341918.1	E9PD35
FLT4	NM_002020.5		c.1258+14G>A	intron	N/A	NP_002011.2	P35916-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FLT4	ENST00000261937.11	TSL:1 MANE Select	c.1258+14G>A	intron	N/A	ENSP00000261937.6	P35916-2
FLT4	ENST00000502649.5	TSL:1	c.1258+14G>A	intron	N/A	ENSP00000426057.1	E9PD35
FLT4	ENST00000393347.7	TSL:1	c.1258+14G>A	intron	N/A	ENSP00000377016.3	P35916-1

Frequencies

GnomAD3 genomes

AF:

0.0443

AC:

6744

AN:

152120

Hom.:

208

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0516

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0302

Gnomad ASJ

AF:

0.0931

Gnomad EAS

AF:

0.183

Gnomad SAS

AF:

0.0891

Gnomad FIN

AF:

0.0220

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0310

Gnomad OTH

AF:

0.0417

GnomAD2 exomes

AF:

0.0528

AC:

13138

AN:

249044

AF XY:

0.0541

show subpopulations

Gnomad AFR exome

AF:

0.0517

Gnomad AMR exome

AF:

0.0312

Gnomad ASJ exome

AF:

0.0918

Gnomad EAS exome

AF:

0.182

Gnomad FIN exome

AF:

0.0214

Gnomad NFE exome

AF:

0.0322

Gnomad OTH exome

AF:

0.0529

GnomAD4 exome

AF:

0.0404

AC:

59031

AN:

1460480

Hom.:

1789

Cov.:

AF XY:

0.0416

AC XY:

30191

AN XY:

726526

show subpopulations

African (AFR)

AF:

0.0504

AC:

1688

AN:

33480

American (AMR)

AF:

0.0320

AC:

1430

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0903

AC:

2359

AN:

26132

East Asian (EAS)

AF:

0.178

AC:

7052

AN:

39700

South Asian (SAS)

AF:

0.0829

AC:

7148

AN:

86256

European-Finnish (FIN)

AF:

0.0229

AC:

1193

AN:

52070

Middle Eastern (MID)

AF:

0.0536

AC:

309

AN:

5768

European-Non Finnish (NFE)

AF:

0.0314

AC:

34867

AN:

1111980

Other (OTH)

AF:

0.0494

AC:

2985

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

3898

7796

11694

15592

19490

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1492

2984

4476

5968

7460

<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:

0.0444

AC:

6753

AN:

152238

Hom.:

210

Cov.:

AF XY:

0.0449

AC XY:

3339

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0517

AC:

2147

AN:

41550

American (AMR)

AF:

0.0301

AC:

461

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0931

AC:

323

AN:

3470

East Asian (EAS)

AF:

0.183

AC:

946

AN:

5170

South Asian (SAS)

AF:

0.0886

AC:

427

AN:

4822

European-Finnish (FIN)

AF:

0.0220

AC:

234

AN:

10618

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0310

AC:

2108

AN:

67996

Other (OTH)

AF:

0.0427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

325

649

974

1298

1623

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

240

320

400

<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:

0.0412

Hom.:

Bravo

AF:

0.0466

Asia WGS

AF:

0.113

AC:

391

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

2.8

(source)

DANN

Benign

0.53

PhyloP100

-0.28

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over