chr5-180621014-G-A

Variant names:

• chr5-180621014-G-A
• rs376156787
• NM_182925.5:c.2168-7C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_182925.5(FLT4):​c.2168-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,611,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: FLT4 NM_182925.5 splice_region, intron
• Scores: Splicing: ADA: 0.00005298
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.385
• Publications: 0 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BS2: High AC in GnomAd4 at 10 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.2168-7C>T		splice_region intron	N/A	NP_891555.2	P35916-2
	FLT4	NM_001354989.2		c.2168-7C>T		splice_region intron	N/A	NP_001341918.1	E9PD35
	FLT4	NM_002020.5		c.2168-7C>T		splice_region intron	N/A	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.2168-7C>T		splice_region intron	N/A	ENSP00000261937.6	P35916-2
	FLT4	ENST00000502649.5	TSL:1	c.2168-7C>T		splice_region intron	N/A	ENSP00000426057.1	E9PD35
	FLT4	ENST00000393347.7	TSL:1	c.2168-7C>T		splice_region intron	N/A	ENSP00000377016.3	P35916-1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152222 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000243 AC: 6 AN: 246448 AF XY: 0.00000744

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000902

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1459092 Hom.: 0 Cov.: 43 AF XY: 0.00000689 AC XY: 5 AN XY: 725626

African (AFR) AF: 0.000209 AC: 7 AN: 33454

American (AMR) AF: 0.0000448 AC: 2 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110942

Other (OTH) AF: 0.0000332 AC: 2 AN: 60288

GnomAD4 genome AF: 0.0000656 AC: 10 AN: 152340 Hom.: 0 Cov.: 34 AF XY: 0.0000806 AC XY: 6 AN XY: 74486

African (AFR) AF: 0.000216 AC: 9 AN: 41592

American (AMR) AF: 0.00 AC: 0 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000102

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.0
DANN	Benign	0.81
PhyloP100		-0.39

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000053
dbscSNV1_RF	Benign	0.0
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: rs376156787; hg19: chr5-180048014;