5-180603322-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_182925.5(FLT4):c.3962G>A(p.Arg1321Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,612,680 control chromosomes in the GnomAD database, including 192 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1321W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0093 (14 hom., cov: 33)
  • Exomes 𝑓: 0.015 (178 hom.)
• Consequence: FLT4 NM_182925.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.776

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=0.0055611134).
• BP6: Variant 5-180603322-C-T is Benign according to our data. Variant chr5-180603322-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 263055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-180603322-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00927 (1412/152360) while in subpopulation NFE AF= 0.0163 (1108/68020). AF 95% confidence interval is 0.0155. There are 14 homozygotes in gnomad4. There are 639 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLT4	NM_182925.5	c.3962G>A	p.Arg1321Gln	missense_variant	30/30	ENST00000261937.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLT4	ENST00000261937.11	c.3962G>A	p.Arg1321Gln	missense_variant	30/30	1	NM_182925.5	P1
FLT4	ENST00000502603.5	n.662G>A		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.00929 AC: 1414 AN: 152242 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.00282

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00602

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0163

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00891 AC: 2201 AN: 247058 Hom.: 17 AF XY: 0.00876 AC XY: 1175 AN XY: 134092

Gnomad AFR exome AF: 0.00233

Gnomad AMR exome AF: 0.00587

Gnomad ASJ exome AF: 0.000698

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00279

Gnomad FIN exome AF: 0.00777

Gnomad NFE exome AF: 0.0149

Gnomad OTH exome AF: 0.00990

GnomAD4 exome AF: 0.0146 AC: 21327 AN: 1460320 Hom.: 178 Cov.: 32 AF XY: 0.0142 AC XY: 10333 AN XY: 726496

Gnomad4 AFR exome AF: 0.00203

Gnomad4 AMR exome AF: 0.00604

Gnomad4 ASJ exome AF: 0.000842

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00287

Gnomad4 FIN exome AF: 0.00852

Gnomad4 NFE exome AF: 0.0176

Gnomad4 OTH exome AF: 0.0113

GnomAD4 genome AF: 0.00927 AC: 1412 AN: 152360 Hom.: 14 Cov.: 33 AF XY: 0.00858 AC XY: 639 AN XY: 74500

Gnomad4 AFR AF: 0.00281

Gnomad4 AMR AF: 0.00555

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00393

Gnomad4 FIN AF: 0.00602

Gnomad4 NFE AF: 0.0163

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.0129 Hom.: 11

Bravo AF: 0.00920

TwinsUK AF: 0.0191 AC: 71

ALSPAC AF: 0.0192 AC: 74

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0164 AC: 141

ExAC AF: 0.00956 AC: 1160

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	7.1
Dann	Benign	0.96
DEOGEN2	Benign	0.086	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.080
Sift	Benign	0.19	T
Sift4G	Benign	0.63	T
Polyphen		0.0010	B
Vest4		0.11
MVP		0.093
MPC		0.13
ClinPred		0.0062	T
GERP RS		1.4
Varity_R		0.027
gMVP		0.25

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: rs79620092; hg19: chr5-180030322; COSMIC: COSV56126176; COSMIC: COSV56126176;