rs79620092

Variant names:

• chr5-180603322-C-T
• rs79620092
• NM_182925.5:c.3962G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-180603322-C-T
• chr5-180603322-C-A

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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:3
• Conservation: PhyloP100: 0.776
• Publications: 11 publications found

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]

FLT4 Gene-Disease associations (from GenCC):

• congenital heart defects, multiple types, 7

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• lymphatic malformation 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• capillary infantile hemangioma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• lymphatic malformation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• tetralogy of fallot

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 263055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1412 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182925.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT4	NM_182925.5	MANE Select	c.3962G>A	p.Arg1321Gln	missense	Exon 30 of 30	NP_891555.2	P35916-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT4	ENST00000261937.11	TSL:1 MANE Select	c.3962G>A	p.Arg1321Gln	missense	Exon 30 of 30	ENSP00000261937.6	P35916-2
	FLT4	ENST00000955857.1		c.4238G>A	p.Arg1413Gln	missense	Exon 30 of 30	ENSP00000625916.1
	FLT4	ENST00000861588.1		c.4028G>A	p.Arg1343Gln	missense	Exon 30 of 30	ENSP00000531647.1

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

GnomAD2 exomes AF: 0.00891 AC: 2201 AN: 247058 AF XY: 0.00876

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 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

African (AFR) AF: 0.00203 AC: 68 AN: 33464

American (AMR) AF: 0.00604 AC: 270 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.000842 AC: 22 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00287 AC: 247 AN: 86150

European-Finnish (FIN) AF: 0.00852 AC: 454 AN: 53310

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5748

European-Non Finnish (NFE) AF: 0.0176 AC: 19568 AN: 1110818

Other (OTH) AF: 0.0113 AC: 682 AN: 60330

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

African (AFR) AF: 0.00281 AC: 117 AN: 41594

American (AMR) AF: 0.00555 AC: 85 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00393 AC: 19 AN: 4832

European-Finnish (FIN) AF: 0.00602 AC: 64 AN: 10632

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0163 AC: 1108 AN: 68020

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.0123 Hom.: 16

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.78
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
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

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