rs307826

Variant names:

• chr5-180624003-T-C
• rs307826
• NM_182925.5:c.1480A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-180624003-T-C
• chr5-180624003-T-A
• chr5-180624003-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182925.5(FLT4):​c.1480A>G​(p.Thr494Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,613,348 control chromosomes in the GnomAD database, including 9,742 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T494M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.081 (638 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9104 hom.)
• Consequence: FLT4 NM_182925.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.603
• Publications: 68 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=0.0014604032).
• BP6: Variant 5-180624003-T-C is Benign according to our data. Variant chr5-180624003-T-C is described in ClinVar as Benign. ClinVar VariationId is 263028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

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.1480A>G	p.Thr494Ala	missense	Exon 11 of 30	NP_891555.2	P35916-2
	FLT4	NM_001354989.2		c.1480A>G	p.Thr494Ala	missense	Exon 11 of 30	NP_001341918.1	E9PD35
	FLT4	NM_002020.5		c.1480A>G	p.Thr494Ala	missense	Exon 11 of 30	NP_002011.2	P35916-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT4	ENST00000261937.11	TSL:1 MANE Select	c.1480A>G	p.Thr494Ala	missense	Exon 11 of 30	ENSP00000261937.6	P35916-2
	FLT4	ENST00000502649.5	TSL:1	c.1480A>G	p.Thr494Ala	missense	Exon 11 of 30	ENSP00000426057.1	E9PD35
	FLT4	ENST00000393347.7	TSL:1	c.1480A>G	p.Thr494Ala	missense	Exon 11 of 30	ENSP00000377016.3	P35916-1

Frequencies

GnomAD3 genomes AF: 0.0813 AC: 12367 AN: 152128 Hom.: 638 Cov.: 32

Gnomad AFR AF: 0.0289

Gnomad AMI AF: 0.304

Gnomad AMR AF: 0.0701

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0773

Gnomad FIN AF: 0.0845

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.0850

GnomAD2 exomes AF: 0.0886 AC: 22186 AN: 250354 AF XY: 0.0925

Gnomad AFR exome AF: 0.0261

Gnomad AMR exome AF: 0.0537

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.0906

Gnomad NFE exome AF: 0.120

Gnomad OTH exome AF: 0.0952

GnomAD4 exome AF: 0.108 AC: 157909 AN: 1461102 Hom.: 9104 Cov.: 33 AF XY: 0.108 AC XY: 78212 AN XY: 726860

African (AFR) AF: 0.0261 AC: 874 AN: 33476

American (AMR) AF: 0.0566 AC: 2530 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 2938 AN: 26134

East Asian (EAS) AF: 0.000529 AC: 21 AN: 39700

South Asian (SAS) AF: 0.0863 AC: 7444 AN: 86258

European-Finnish (FIN) AF: 0.0899 AC: 4744 AN: 52742

Middle Eastern (MID) AF: 0.0952 AC: 549 AN: 5768

European-Non Finnish (NFE) AF: 0.119 AC: 132848 AN: 1111920

Other (OTH) AF: 0.0987 AC: 5961 AN: 60386

GnomAD4 genome AF: 0.0812 AC: 12366 AN: 152246 Hom.: 638 Cov.: 32 AF XY: 0.0794 AC XY: 5915 AN XY: 74458

African (AFR) AF: 0.0289 AC: 1200 AN: 41544

American (AMR) AF: 0.0700 AC: 1071 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 416 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5184

South Asian (SAS) AF: 0.0770 AC: 371 AN: 4820

European-Finnish (FIN) AF: 0.0845 AC: 897 AN: 10610

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.117 AC: 7924 AN: 68006

Other (OTH) AF: 0.0841 AC: 178 AN: 2116

Alfa AF: 0.104 Hom.: 2238

Bravo AF: 0.0784

TwinsUK AF: 0.121 AC: 448

ALSPAC AF: 0.117 AC: 449

ESP6500AA AF: 0.0300 AC: 132

ESP6500EA AF: 0.123 AC: 1055

ExAC AF: 0.0898 AC: 10901

Asia WGS AF: 0.0460 AC: 159 AN: 3478

EpiCase AF: 0.124

EpiControl AF: 0.122

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	10
DANN	Benign	0.80
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.60
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.13
Sift	Benign	0.23	T
Sift4G	Benign	0.77	T
Polyphen		0.0	B
Vest4		0.10
MPC		0.59
ClinPred		0.0030	T
GERP RS		2.3
Varity_R		0.21
gMVP		0.25
Mutation Taster		=97/3	polymorphism (auto)

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: rs307826; hg19: chr5-180051003; COSMIC: COSV56108373; COSMIC: COSV56108373;