rs307821

chr5-180603313-C-Achr5-180603313-C-Gchr5-180603313-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182925.5(FLT4):c.3971G>T(p.Arg1324Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0968 in 1,613,696 control chromosomes in the GnomAD database, including 8,130 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1324P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.081 (567 hom., cov: 33)
  • Exomes 𝑓: 0.099 (7563 hom.)
• Consequence: FLT4 NM_182925.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.34

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015855432).
• BP6: Variant 5-180603313-C-A is Benign according to our data. Variant chr5-180603313-C-A is described in ClinVar as [Benign]. Clinvar id is 263057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-180603313-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLT4	NM_182925.5	c.3971G>T	p.Arg1324Leu	missense_variant	30/30	ENST00000261937.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLT4	ENST00000261937.11	c.3971G>T	p.Arg1324Leu	missense_variant	30/30	1	NM_182925.5	P1
FLT4	ENST00000502603.5	n.671G>T		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.0806 AC: 12274 AN: 152246 Hom.: 567 Cov.: 33

Gnomad AFR AF: 0.0512

Gnomad AMI AF: 0.297

Gnomad AMR AF: 0.0613

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0409

Gnomad FIN AF: 0.0860

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.0755

GnomAD3 exomes AF: 0.0786 AC: 19397 AN: 246898 Hom.: 926 AF XY: 0.0794 AC XY: 10635 AN XY: 133964

Gnomad AFR exome AF: 0.0535

Gnomad AMR exome AF: 0.0448

Gnomad ASJ exome AF: 0.0986

Gnomad EAS exome AF: 0.000656

Gnomad SAS exome AF: 0.0441

Gnomad FIN exome AF: 0.0940

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.0845

GnomAD4 exome AF: 0.0985 AC: 143954 AN: 1461332 Hom.: 7563 Cov.: 32 AF XY: 0.0968 AC XY: 70361 AN XY: 726924

Gnomad4 AFR exome AF: 0.0525

Gnomad4 AMR exome AF: 0.0471

Gnomad4 ASJ exome AF: 0.101

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.0465

Gnomad4 FIN exome AF: 0.0925

Gnomad4 NFE exome AF: 0.110

Gnomad4 OTH exome AF: 0.0882

GnomAD4 genome AF: 0.0806 AC: 12283 AN: 152364 Hom.: 567 Cov.: 33 AF XY: 0.0790 AC XY: 5889 AN XY: 74512

Gnomad4 AFR AF: 0.0513

Gnomad4 AMR AF: 0.0612

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0408

Gnomad4 FIN AF: 0.0860

Gnomad4 NFE AF: 0.107

Gnomad4 OTH AF: 0.0747

Alfa AF: 0.0742 Hom.: 158

Bravo AF: 0.0794

TwinsUK AF: 0.119 AC: 442

ALSPAC AF: 0.107 AC: 413

ESP6500AA AF: 0.0522 AC: 230

ESP6500EA AF: 0.109 AC: 934

ExAC AF: 0.0803 AC: 9752

EpiCase AF: 0.111

EpiControl AF: 0.108

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	0.0060
Dann	Benign	0.39
DEOGEN2	Benign	0.078	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.068
Sift	Benign	0.65	T
Sift4G	Benign	0.66	T
Polyphen		0.0	B
Vest4		0.023
MPC		0.14
ClinPred		0.00030	T
GERP RS		-8.8
Varity_R		0.029
gMVP		0.13

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: rs307821; hg19: chr5-180030313; COSMIC: COSV56108334; COSMIC: COSV56108334;