chr5-180626307-A-G

Variant names:

• chr5-180626307-A-G
• rs402647
• NM_182925.5:c.1104-42T>C

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.1104-42T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.989 in 1,603,688 control chromosomes in the GnomAD database, including 785,703 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (68044 hom., cov: 31)
  • Exomes 𝑓: 0.99 (717659 hom.)
• Consequence: FLT4 NM_182925.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.63
• Publications: 7 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):

• lymphatic malformation 1

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

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• congenital heart defects, multiple types, 7

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• 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 (BayesDel_noAF=-0.89).
• BP6: Variant 5-180626307-A-G is Benign according to our data. Variant chr5-180626307-A-G is described in ClinVar as Benign. ClinVar VariationId is 263020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 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.1104-42T>C		intron	N/A	NP_891555.2
	FLT4	NM_001354989.2		c.1104-42T>C		intron	N/A	NP_001341918.1
	FLT4	NM_002020.5		c.1104-42T>C		intron	N/A	NP_002011.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT4	ENST00000261937.11	TSL:1 MANE Select	c.1104-42T>C		intron	N/A	ENSP00000261937.6
	FLT4	ENST00000502649.5	TSL:1	c.1104-42T>C		intron	N/A	ENSP00000426057.1
	FLT4	ENST00000393347.7	TSL:1	c.1104-42T>C		intron	N/A	ENSP00000377016.3

Frequencies

GnomAD3 genomes AF: 0.942 AC: 143155 AN: 152020 Hom.: 67997 Cov.: 31

Gnomad AFR AF: 0.798

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.975

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.984

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.957

GnomAD2 exomes AF: 0.984 AC: 238397 AN: 242190 AF XY: 0.988

Gnomad AFR exome AF: 0.790

Gnomad AMR exome AF: 0.990

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.994

GnomAD4 exome AF: 0.994 AC: 1442638 AN: 1451550 Hom.: 717659 Cov.: 37 AF XY: 0.995 AC XY: 718705 AN XY: 722494

African (AFR) AF: 0.788 AC: 26346 AN: 33428

American (AMR) AF: 0.988 AC: 44181 AN: 44710

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26126 AN: 26126

East Asian (EAS) AF: 1.00 AC: 39686 AN: 39686

South Asian (SAS) AF: 1.00 AC: 86181 AN: 86212

European-Finnish (FIN) AF: 1.00 AC: 44828 AN: 44830

Middle Eastern (MID) AF: 0.990 AC: 5675 AN: 5730

European-Non Finnish (NFE) AF: 1.00 AC: 1110112 AN: 1110556

Other (OTH) AF: 0.987 AC: 59503 AN: 60272

GnomAD4 genome AF: 0.942 AC: 143260 AN: 152138 Hom.: 68044 Cov.: 31 AF XY: 0.944 AC XY: 70255 AN XY: 74388

African (AFR) AF: 0.798 AC: 33053 AN: 41418

American (AMR) AF: 0.975 AC: 14925 AN: 15302

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5177 AN: 5178

South Asian (SAS) AF: 1.00 AC: 4810 AN: 4812

European-Finnish (FIN) AF: 1.00 AC: 10624 AN: 10624

Middle Eastern (MID) AF: 0.983 AC: 289 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67975 AN: 68014

Other (OTH) AF: 0.958 AC: 2023 AN: 2112

Alfa AF: 0.987 Hom.: 7959

Bravo AF: 0.933

Asia WGS AF: 0.990 AC: 3443 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital heart defects, multiple types, 7 (1)
-	-	1	Hereditary lymphedema type I (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.1
DANN	Benign	0.57
PhyloP100		-1.6
Mutation Taster		=100/0	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: rs402647; hg19: chr5-180053307;