rs659268

Variant names:

• chr5-180614208-T-C
• rs659268
• NM_182925.5:c.3220-29A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182925.5(FLT4):​c.3220-29A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.753 in 1,286,228 control chromosomes in the GnomAD database, including 360,821 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (34377 hom., cov: 27)
  • Exomes 𝑓: 0.75 (326444 hom.)
• Consequence: FLT4 NM_182925.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.96
• Publications: 8 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 5-180614208-T-C is Benign according to our data. Variant chr5-180614208-T-C is described in ClinVar as Benign. ClinVar VariationId is 263049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.81 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT4	NM_182925.5	MANE Select	c.3220-29A>G		intron	N/A	NP_891555.2	P35916-2
	FLT4	NM_001354989.2		c.3220-29A>G		intron	N/A	NP_001341918.1	E9PD35
	FLT4	NM_002020.5		c.3220-29A>G		intron	N/A	NP_002011.2	P35916-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT4	ENST00000261937.11	TSL:1 MANE Select	c.3220-29A>G		intron	N/A	ENSP00000261937.6	P35916-2
	FLT4	ENST00000502649.5	TSL:1	c.3220-29A>G		intron	N/A	ENSP00000426057.1	E9PD35
	FLT4	ENST00000393347.7	TSL:1	c.3220-29A>G		intron	N/A	ENSP00000377016.3	P35916-1

Frequencies

GnomAD3 genomes AF: 0.763 AC: 94348 AN: 123644 Hom.: 34362 Cov.: 27

Gnomad AFR AF: 0.692

Gnomad AMI AF: 0.818

Gnomad AMR AF: 0.823

Gnomad ASJ AF: 0.771

Gnomad EAS AF: 0.643

Gnomad SAS AF: 0.764

Gnomad FIN AF: 0.811

Gnomad MID AF: 0.754

Gnomad NFE AF: 0.794

Gnomad OTH AF: 0.762

GnomAD2 exomes AF: 0.723 AC: 152660 AN: 211094 AF XY: 0.716

Gnomad AFR exome AF: 0.644

Gnomad AMR exome AF: 0.808

Gnomad ASJ exome AF: 0.693

Gnomad EAS exome AF: 0.569

Gnomad FIN exome AF: 0.762

Gnomad NFE exome AF: 0.743

Gnomad OTH exome AF: 0.729

GnomAD4 exome AF: 0.752 AC: 874231 AN: 1162452 Hom.: 326444 Cov.: 19 AF XY: 0.750 AC XY: 435759 AN XY: 580772

African (AFR) AF: 0.661 AC: 17919 AN: 27092

American (AMR) AF: 0.804 AC: 32787 AN: 40778

Ashkenazi Jewish (ASJ) AF: 0.717 AC: 15467 AN: 21574

East Asian (EAS) AF: 0.605 AC: 20412 AN: 33712

South Asian (SAS) AF: 0.709 AC: 47177 AN: 66558

European-Finnish (FIN) AF: 0.796 AC: 36790 AN: 46194

Middle Eastern (MID) AF: 0.660 AC: 3029 AN: 4588

European-Non Finnish (NFE) AF: 0.761 AC: 665062 AN: 874070

Other (OTH) AF: 0.743 AC: 35588 AN: 47886

GnomAD4 genome AF: 0.763 AC: 94418 AN: 123776 Hom.: 34377 Cov.: 27 AF XY: 0.763 AC XY: 46095 AN XY: 60390

African (AFR) AF: 0.692 AC: 24243 AN: 35030

American (AMR) AF: 0.823 AC: 10398 AN: 12634

Ashkenazi Jewish (ASJ) AF: 0.771 AC: 2024 AN: 2626

East Asian (EAS) AF: 0.642 AC: 2443 AN: 3806

South Asian (SAS) AF: 0.763 AC: 2642 AN: 3464

European-Finnish (FIN) AF: 0.811 AC: 7076 AN: 8728

Middle Eastern (MID) AF: 0.736 AC: 162 AN: 220

European-Non Finnish (NFE) AF: 0.794 AC: 43507 AN: 54790

Other (OTH) AF: 0.757 AC: 1290 AN: 1704

Alfa AF: 0.570 Hom.: 990

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital heart defects, multiple types, 7 (1)
-	-	1	Hereditary lymphedema type I (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.040
DANN	Benign	0.33
PhyloP100		-3.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs659268; hg19: chr5-180041208; COSMIC: COSV56097287; COSMIC: COSV56097287;