5-180603329-G-C

Variant names:

• chr5-180603329-G-C
• rs142322370
• NM_182925.5:c.3955C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_182925.5(FLT4):​c.3955C>G​(p.Arg1319Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1319W) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLT4 NM_182925.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.283
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04317358).

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.3955C>G	p.Arg1319Gly	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.3955C>G	p.Arg1319Gly	missense	Exon 30 of 30	ENSP00000261937.6	P35916-2
	FLT4	ENST00000955857.1		c.4231C>G	p.Arg1411Gly	missense	Exon 30 of 30	ENSP00000625916.1
	FLT4	ENST00000861588.1		c.4021C>G	p.Arg1341Gly	missense	Exon 30 of 30	ENSP00000531647.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	9.3
DANN	Benign	0.92
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.28
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.12
Sift	Benign	0.42	T
Sift4G	Benign	0.50	T
Polyphen		0.079	B
Vest4		0.19
MutPred		0.21		Gain of methylation at R1320 (P = 0.0627)
MVP		0.10
MPC		0.16
ClinPred		0.051	T
GERP RS		1.1
Varity_R		0.032
gMVP		0.18
Mutation Taster		=91/9	polymorphism

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: rs142322370; hg19: chr5-180030329;