5-180612606-C-T

Position:

• chr5-180612606-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.3437G>A​(p.Arg1146His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0942 in 1,611,386 control chromosomes in the GnomAD database, including 8,199 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1146G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.071 (544 hom., cov: 32)
  • Exomes 𝑓: 0.097 (7655 hom.)
• Consequence: FLT4 NM_182925.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.746

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=0.00330472).
• BP6: Variant 5-180612606-C-T is Benign according to our data. Variant chr5-180612606-C-T is described in ClinVar as [Benign]. Clinvar id is 263050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-180612606-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLT4	NM_182925.5	c.3437G>A	p.Arg1146His	missense_variant	26/30	ENST00000261937.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLT4	ENST00000261937.11	c.3437G>A	p.Arg1146His	missense_variant	26/30	1	NM_182925.5	P1

Frequencies

GnomAD3 genomes AF: 0.0715 AC: 10873 AN: 152046 Hom.: 544 Cov.: 32

Gnomad AFR AF: 0.0192

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.0460

Gnomad ASJ AF: 0.0776

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0321

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.0675

GnomAD3 exomes AF: 0.0748 AC: 18772 AN: 251056 Hom.: 970 AF XY: 0.0747 AC XY: 10137 AN XY: 135762

Gnomad AFR exome AF: 0.0161

Gnomad AMR exome AF: 0.0352

Gnomad ASJ exome AF: 0.0867

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0347

Gnomad FIN exome AF: 0.122

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.0783

GnomAD4 exome AF: 0.0966 AC: 140933 AN: 1459222 Hom.: 7655 Cov.: 31 AF XY: 0.0947 AC XY: 68746 AN XY: 726100

Gnomad4 AFR exome AF: 0.0151

Gnomad4 AMR exome AF: 0.0371

Gnomad4 ASJ exome AF: 0.0868

Gnomad4 EAS exome AF: 0.000327

Gnomad4 SAS exome AF: 0.0364

Gnomad4 FIN exome AF: 0.126

Gnomad4 NFE exome AF: 0.109

Gnomad4 OTH exome AF: 0.0836

GnomAD4 genome AF: 0.0714 AC: 10869 AN: 152164 Hom.: 544 Cov.: 32 AF XY: 0.0689 AC XY: 5121 AN XY: 74374

Gnomad4 AFR AF: 0.0191

Gnomad4 AMR AF: 0.0459

Gnomad4 ASJ AF: 0.0776

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0324

Gnomad4 FIN AF: 0.121

Gnomad4 NFE AF: 0.108

Gnomad4 OTH AF: 0.0668

Alfa AF: 0.0978 Hom.: 1229

Bravo AF: 0.0641

TwinsUK AF: 0.111 AC: 413

ALSPAC AF: 0.113 AC: 435

ESP6500AA AF: 0.0216 AC: 95

ESP6500EA AF: 0.100 AC: 860

ExAC AF: 0.0755 AC: 9163

Asia WGS AF: 0.0140 AC: 47 AN: 3478

EpiCase AF: 0.0922

EpiControl AF: 0.102

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	10
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T;.;T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.59	T;T;T
MetaRNN	Benign	0.0033	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.63	N;N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.25	N;N;N
REVEL	Benign	0.094
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.0020	B;.;B
Vest4		0.11
MPC		0.76
ClinPred		0.0015	T
GERP RS		-0.63
Varity_R		0.031
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1130379; hg19: chr5-180039606; COSMIC: COSV56097140; COSMIC: COSV56097140;