chr5-180603221-C-G

Variant names:

• chr5-180603221-C-G
• rs143739828
• NM_182925.5:c.4063G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_182925.5(FLT4):​c.4063G>C​(p.Val1355Leu) 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. 16/21 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. V1355M) 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: -2.53

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06404632).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLT4	NM_182925.5	c.4063G>C	p.Val1355Leu	missense_variant	Exon 30 of 30	ENST00000261937.11	NP_891555.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLT4	ENST00000261937.11	c.4063G>C	p.Val1355Leu	missense_variant	Exon 30 of 30	1	NM_182925.5	ENSP00000261937.6
FLT4	ENST00000502603.5	n.763G>C		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.55
DANN	Benign	0.77
DEOGEN2	Benign	0.083	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.15
Sift	Benign	0.13	T
Sift4G	Benign	0.12	T
Polyphen		0.033	B
Vest4		0.046
MutPred		0.12		Loss of glycosylation at S1352 (P = 0.102);
MVP		0.27
MPC		0.12
ClinPred		0.078	T
GERP RS		-4.7
Varity_R		0.036
gMVP		0.21

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

LitVar

Other links and lift over

dbSNP: rs143739828; hg19: chr5-180030221;