chr5-180630371-C-T

Variant names:

• chr5-180630371-C-T
• rs77918653
• NM_182925.5:c.401-34G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_182925.5(FLT4):​c.401-34G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,590,652 control chromosomes in the GnomAD database, including 272 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (21 hom., cov: 32)
  • Exomes 𝑓: 0.017 (251 hom.)
• Consequence: FLT4 NM_182925.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.91
• 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):

• 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 5-180630371-C-T is Benign according to our data. Variant chr5-180630371-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 263061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0126 (1912/152206) while in subpopulation NFE AF = 0.0184 (1250/67994). AF 95% confidence interval is 0.0175. There are 21 homozygotes in GnomAd4. There are 946 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1912 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT4	NM_182925.5	MANE Select	c.401-34G>A		intron	N/A	NP_891555.2
	FLT4	NM_001354989.2		c.401-34G>A		intron	N/A	NP_001341918.1
	FLT4	NM_002020.5		c.401-34G>A		intron	N/A	NP_002011.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLT4	ENST00000261937.11	TSL:1 MANE Select	c.401-34G>A		intron	N/A	ENSP00000261937.6
	FLT4	ENST00000502649.5	TSL:1	c.401-34G>A		intron	N/A	ENSP00000426057.1
	FLT4	ENST00000393347.7	TSL:1	c.401-34G>A		intron	N/A	ENSP00000377016.3

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1912 AN: 152088 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.00343

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.0283

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0184

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0127 AC: 3045 AN: 239934 AF XY: 0.0128

Gnomad AFR exome AF: 0.00299

Gnomad AMR exome AF: 0.00735

Gnomad ASJ exome AF: 0.0270

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.0113

Gnomad NFE exome AF: 0.0187

Gnomad OTH exome AF: 0.0156

GnomAD4 exome AF: 0.0167 AC: 23982 AN: 1438446 Hom.: 251 Cov.: 31 AF XY: 0.0163 AC XY: 11711 AN XY: 716556

African (AFR) AF: 0.00292 AC: 97 AN: 33232

American (AMR) AF: 0.00757 AC: 338 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.0287 AC: 747 AN: 26054

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39606

South Asian (SAS) AF: 0.00504 AC: 433 AN: 85952

European-Finnish (FIN) AF: 0.0100 AC: 433 AN: 43102

Middle Eastern (MID) AF: 0.0207 AC: 119 AN: 5746

European-Non Finnish (NFE) AF: 0.0189 AC: 20791 AN: 1100242

Other (OTH) AF: 0.0170 AC: 1020 AN: 59890

GnomAD4 genome AF: 0.0126 AC: 1912 AN: 152206 Hom.: 21 Cov.: 32 AF XY: 0.0127 AC XY: 946 AN XY: 74410

African (AFR) AF: 0.00342 AC: 142 AN: 41536

American (AMR) AF: 0.0158 AC: 242 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0283 AC: 98 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4822

European-Finnish (FIN) AF: 0.0107 AC: 114 AN: 10610

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0184 AC: 1250 AN: 67994

Other (OTH) AF: 0.0185 AC: 39 AN: 2108

Alfa AF: 0.0158 Hom.: 2

Bravo AF: 0.0121

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.073
DANN	Benign	0.43
PhyloP100		-2.9
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs77918653; hg19: chr5-180057371;