chr5-180603364-G-A

Variant names:

• chr5-180603364-G-A
• rs2127781827
• NM_182925.5:c.3920C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_182925.5(FLT4):​c.3920C>T​(p.Ala1307Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FLT4 NM_182925.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.32
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07709953).

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.3920C>T	p.Ala1307Val	missense	Exon 30 of 30	NP_891555.2	P35916-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT4	ENST00000261937.11	TSL:1 MANE Select	c.3920C>T	p.Ala1307Val	missense	Exon 30 of 30	ENSP00000261937.6	P35916-2
	FLT4	ENST00000955857.1		c.4196C>T	p.Ala1399Val	missense	Exon 30 of 30	ENSP00000625916.1
	FLT4	ENST00000861588.1		c.3986C>T	p.Ala1329Val	missense	Exon 30 of 30	ENSP00000531647.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461708 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727136

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111954

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.34	N
PhyloP100		2.3
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.15
Sift	Uncertain	0.016	D
Sift4G	Benign	0.33	T
Polyphen		0.0030	B
Vest4		0.034
MutPred		0.11		Gain of MoRF binding (P = 0.1338)
MVP		0.043
MPC		0.12
ClinPred		0.17	T
GERP RS		2.2
Varity_R		0.045
gMVP		0.087
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2127781827; hg19: chr5-180030364; COSMIC: COSV99987515; COSMIC: COSV99987515;