rs2934602

Variant names:

• chr5-180614190-A-G
• rs2934602
• NM_182925.5:c.3220-11T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_182925.5(FLT4):​c.3220-11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,245,446 control chromosomes in the GnomAD database, including 1 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: FLT4 NM_182925.5 intron
• Scores: Splicing: ADA: 0.00003814
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.90
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 5-180614190-A-G is Benign according to our data. Variant chr5-180614190-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 263047.Status of the report is criteria_provided_single_submitter, 1 stars.

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.3220-11T>C		intron	N/A	NP_891555.2	P35916-2
	FLT4	NM_001354989.2		c.3220-11T>C		intron	N/A	NP_001341918.1	E9PD35
	FLT4	NM_002020.5		c.3220-11T>C		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.3220-11T>C		intron	N/A	ENSP00000261937.6	P35916-2
	FLT4	ENST00000502649.5	TSL:1	c.3220-11T>C		intron	N/A	ENSP00000426057.1	E9PD35
	FLT4	ENST00000393347.7	TSL:1	c.3220-11T>C		intron	N/A	ENSP00000377016.3	P35916-1

Frequencies

GnomAD3 genomes AF: 0.000609 AC: 35 AN: 57500 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000216

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: 0.0000413

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000703 AC: 147 AN: 209044 AF XY: 0.000596

Gnomad AFR exome AF: 0.00664

Gnomad AMR exome AF: 0.000952

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000839

Gnomad OTH exome AF: 0.000858

GnomAD4 exome AF: 0.000198 AC: 235 AN: 1187854 Hom.: 1 Cov.: 29 AF XY: 0.000178 AC XY: 104 AN XY: 585158

African (AFR) AF: 0.00482 AC: 131 AN: 27156

American (AMR) AF: 0.000230 AC: 8 AN: 34722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18126

East Asian (EAS) AF: 0.00 AC: 0 AN: 26168

South Asian (SAS) AF: 0.000374 AC: 21 AN: 56176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39228

Middle Eastern (MID) AF: 0.00154 AC: 7 AN: 4542

European-Non Finnish (NFE) AF: 0.0000513 AC: 48 AN: 936508

Other (OTH) AF: 0.000442 AC: 20 AN: 45228

GnomAD4 genome AF: 0.000642 AC: 37 AN: 57592 Hom.: 0 Cov.: 0 AF XY: 0.000790 AC XY: 22 AN XY: 27840

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00174 AC: 35 AN: 20114

American (AMR) AF: 0.000215 AC: 1 AN: 4644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1222

East Asian (EAS) AF: 0.00 AC: 0 AN: 1948

South Asian (SAS) AF: 0.00 AC: 0 AN: 1286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 48

European-Non Finnish (NFE) AF: 0.0000413 AC: 1 AN: 24218

Other (OTH) AF: 0.00 AC: 0 AN: 786

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00398 Hom.: 1

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.10
DANN	Benign	0.29
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.030
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: rs2934602; hg19: chr5-180041190; COSMIC: COSV56098149; COSMIC: COSV56098149;