chr5-180603325-C-T

Variant names:

• chr5-180603325-C-T
• rs115824945
• NM_182925.5:c.3959G>A

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.3959G>A​(p.Arg1320Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00414 in 1,613,938 control chromosomes in the GnomAD database, including 238 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (122 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (116 hom.)
• Consequence: FLT4 NM_182925.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.230
• Publications: 2 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=0.003283918).
• BP6: Variant 5-180603325-C-T is Benign according to our data. Variant chr5-180603325-C-T is described in ClinVar as Benign. ClinVar VariationId is 263054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0747 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.3959G>A	p.Arg1320Gln	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.3959G>A	p.Arg1320Gln	missense	Exon 30 of 30	ENSP00000261937.6	P35916-2
	FLT4	ENST00000955857.1		c.4235G>A	p.Arg1412Gln	missense	Exon 30 of 30	ENSP00000625916.1
	FLT4	ENST00000861588.1		c.4025G>A	p.Arg1342Gln	missense	Exon 30 of 30	ENSP00000531647.1

Frequencies

GnomAD3 genomes AF: 0.0226 AC: 3447 AN: 152254 Hom.: 122 Cov.: 33

Gnomad AFR AF: 0.0771

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.00567 AC: 1402 AN: 247296 AF XY: 0.00408

Gnomad AFR exome AF: 0.0796

Gnomad AMR exome AF: 0.00285

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000208

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.00221 AC: 3237 AN: 1461566 Hom.: 116 Cov.: 32 AF XY: 0.00183 AC XY: 1332 AN XY: 727052

African (AFR) AF: 0.0799 AC: 2675 AN: 33474

American (AMR) AF: 0.00360 AC: 161 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

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

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86196

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53358

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5758

European-Non Finnish (NFE) AF: 0.0000809 AC: 90 AN: 1111912

Other (OTH) AF: 0.00486 AC: 293 AN: 60350

GnomAD4 genome AF: 0.0226 AC: 3449 AN: 152372 Hom.: 122 Cov.: 33 AF XY: 0.0220 AC XY: 1640 AN XY: 74514

African (AFR) AF: 0.0769 AC: 3200 AN: 41588

American (AMR) AF: 0.0131 AC: 200 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68026

Other (OTH) AF: 0.0189 AC: 40 AN: 2116

Alfa AF: 0.00378 Hom.: 34

Bravo AF: 0.0264

ESP6500AA AF: 0.0708 AC: 312

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00676 AC: 821

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

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	0.069
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.4
DANN	Benign	0.97
DEOGEN2	Benign	0.086	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.23
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.092
Sift	Benign	0.37	T
Sift4G	Benign	0.52	T
Polyphen		0.11	B
Vest4		0.10
MVP		0.17
MPC		0.14
ClinPred		0.0015	T
GERP RS		-0.50
Varity_R		0.018
gMVP		0.23
Mutation Taster		=92/8	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: rs115824945; hg19: chr5-180030325; COSMIC: COSV56104884;