NM_182925.5:c.445A>G

Variant names:

• chr5-180630293-T-C
• rs34221241
• NM_182925.5:c.445A>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.445A>G​(p.Asn149Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.092 in 1,612,212 control chromosomes in the GnomAD database, including 7,695 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. N149Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.070 (525 hom., cov: 32)
  • Exomes 𝑓: 0.094 (7170 hom.)
• Consequence: FLT4 NM_182925.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.40
• Publications: 20 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• lymphatic malformation 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P
• 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=0.0018151104).
• BP6: Variant 5-180630293-T-C is Benign according to our data. Variant chr5-180630293-T-C is described in ClinVar as Benign. ClinVar VariationId is 263062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.104 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.445A>G	p.Asn149Asp	missense	Exon 4 of 30	NP_891555.2	P35916-2
	FLT4	NM_001354989.2		c.445A>G	p.Asn149Asp	missense	Exon 4 of 30	NP_001341918.1	E9PD35
	FLT4	NM_002020.5		c.445A>G	p.Asn149Asp	missense	Exon 4 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.445A>G	p.Asn149Asp	missense	Exon 4 of 30	ENSP00000261937.6	P35916-2
	FLT4	ENST00000502649.5	TSL:1	c.445A>G	p.Asn149Asp	missense	Exon 4 of 30	ENSP00000426057.1	E9PD35
	FLT4	ENST00000393347.7	TSL:1	c.445A>G	p.Asn149Asp	missense	Exon 4 of 30	ENSP00000377016.3	P35916-1

Frequencies

GnomAD3 genomes AF: 0.0704 AC: 10715 AN: 152134 Hom.: 525 Cov.: 32

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.0500

Gnomad ASJ AF: 0.0625

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0414

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.0699

GnomAD2 exomes AF: 0.0738 AC: 18397 AN: 249392 AF XY: 0.0745

Gnomad AFR exome AF: 0.0174

Gnomad AMR exome AF: 0.0373

Gnomad ASJ exome AF: 0.0673

Gnomad EAS exome AF: 0.000490

Gnomad FIN exome AF: 0.116

Gnomad NFE exome AF: 0.105

Gnomad OTH exome AF: 0.0751

GnomAD4 exome AF: 0.0943 AC: 137692 AN: 1459960 Hom.: 7170 Cov.: 37 AF XY: 0.0928 AC XY: 67414 AN XY: 726352

African (AFR) AF: 0.0152 AC: 509 AN: 33480

American (AMR) AF: 0.0390 AC: 1744 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0665 AC: 1738 AN: 26130

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39700

South Asian (SAS) AF: 0.0466 AC: 4017 AN: 86256

European-Finnish (FIN) AF: 0.119 AC: 6163 AN: 51734

Middle Eastern (MID) AF: 0.0877 AC: 506 AN: 5768

European-Non Finnish (NFE) AF: 0.106 AC: 118097 AN: 1111810

Other (OTH) AF: 0.0813 AC: 4907 AN: 60364

GnomAD4 genome AF: 0.0704 AC: 10712 AN: 152252 Hom.: 525 Cov.: 32 AF XY: 0.0683 AC XY: 5087 AN XY: 74438

African (AFR) AF: 0.0190 AC: 791 AN: 41560

American (AMR) AF: 0.0498 AC: 762 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0625 AC: 217 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.0417 AC: 201 AN: 4824

European-Finnish (FIN) AF: 0.118 AC: 1254 AN: 10610

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7184 AN: 68002

Other (OTH) AF: 0.0687 AC: 145 AN: 2112

Alfa AF: 0.0794 Hom.: 523

Bravo AF: 0.0632

TwinsUK AF: 0.104 AC: 385

ALSPAC AF: 0.108 AC: 415

ESP6500AA AF: 0.0218 AC: 96

ESP6500EA AF: 0.0975 AC: 838

ExAC AF: 0.0747 AC: 9037

Asia WGS AF: 0.0160 AC: 55 AN: 3478

EpiCase AF: 0.0937

EpiControl AF: 0.101

ClinVar

ClinVar submissions as Germline

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	0.097
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.4
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.064
Sift	Benign	0.19	T
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.061
MPC		0.68
ClinPred		0.0043	T
GERP RS		3.0
Varity_R		0.14
gMVP		0.65
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs34221241; hg19: chr5-180057293; COSMIC: COSV56097170; COSMIC: COSV56097170;