rs34117331

Variant names:

• chr5-180629986-T-C
• rs34117331
• NM_182925.5:c.633A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_182925.5(FLT4):​c.633A>G​(p.Gly211Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00571 in 1,612,830 control chromosomes in the GnomAD database, including 295 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (135 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (160 hom.)
• Consequence: FLT4 NM_182925.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.66
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 5-180629986-T-C is Benign according to our data. Variant chr5-180629986-T-C is described in ClinVar as [Benign]. Clinvar id is 263067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.65 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0716 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLT4	NM_182925.5	c.633A>G	p.Gly211Gly	synonymous_variant	Exon 5 of 30	ENST00000261937.11	NP_891555.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLT4	ENST00000261937.11	c.633A>G	p.Gly211Gly	synonymous_variant	Exon 5 of 30	1	NM_182925.5	ENSP00000261937.6

Frequencies

GnomAD3 genomes AF: 0.0228 AC: 3469 AN: 152162 Hom.: 133 Cov.: 33

Gnomad AFR AF: 0.0737

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0294

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0211

GnomAD2 exomes AF: 0.00921 AC: 2301 AN: 249906 AF XY: 0.00863

Gnomad AFR exome AF: 0.0781

Gnomad AMR exome AF: 0.00414

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.00459

GnomAD4 exome AF: 0.00393 AC: 5737 AN: 1460550 Hom.: 160 Cov.: 38 AF XY: 0.00432 AC XY: 3142 AN XY: 726554

African (AFR) AF: 0.0760 AC: 2546 AN: 33480

American (AMR) AF: 0.00456 AC: 204 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0280 AC: 2417 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52110

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5766

European-Non Finnish (NFE) AF: 0.0000944 AC: 105 AN: 1112002

Other (OTH) AF: 0.00742 AC: 448 AN: 60380

GnomAD4 genome AF: 0.0229 AC: 3480 AN: 152280 Hom.: 135 Cov.: 33 AF XY: 0.0224 AC XY: 1671 AN XY: 74446

African (AFR) AF: 0.0738 AC: 3066 AN: 41550

American (AMR) AF: 0.0141 AC: 215 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0292 AC: 141 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68024

Other (OTH) AF: 0.0208 AC: 44 AN: 2112

Alfa AF: 0.0112 Hom.: 22

Bravo AF: 0.0255

Asia WGS AF: 0.0180 AC: 62 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000237

ClinVar

Significance: 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: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Sep 13, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.55
DANN	Benign	0.44
PhyloP100		-1.7
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: rs34117331; hg19: chr5-180056986; COSMIC: COSV107246724; COSMIC: COSV107246724;