chr5-180616439-G-T

Variant names:

• chr5-180616439-G-T
• rs56127961
• NM_182925.5:c.3147C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_182925.5(FLT4):​c.3147C>A​(p.Asp1049Glu) 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. 12/21 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. D1049N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLT4 NM_182925.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0530

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22633448).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLT4	NM_182925.5	c.3147C>A	p.Asp1049Glu	missense_variant	Exon 23 of 30	ENST00000261937.11	NP_891555.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLT4	ENST00000261937.11	c.3147C>A	p.Asp1049Glu	missense_variant	Exon 23 of 30	1	NM_182925.5	ENSP00000261937.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251186 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T;.;T;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.80	T;T;T;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.38	N;N;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Benign	0.28
Sift	Uncertain	0.0030	D;D;D;T
Sift4G	Uncertain	0.0070	D;D;D;.
Polyphen		0.46	P;.;B;.
Vest4		0.32
MutPred		0.38		Loss of ubiquitination at K1052 (P = 0.0982);Loss of ubiquitination at K1052 (P = 0.0982);Loss of ubiquitination at K1052 (P = 0.0982);.;
MVP		0.26
MPC		0.96
ClinPred		0.29	T
GERP RS		-5.8
Varity_R		0.41
gMVP		0.62

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: rs56127961; hg19: chr5-180043439;