NM_182925.5:c.1103+18C>T

Variant names:

• chr5-180628864-G-A
• rs438464
• NM_182925.5:c.1103+18C>T

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.1103+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.5 in 1,545,306 control chromosomes in the GnomAD database, including 194,988 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (17641 hom., cov: 31)
  • Exomes 𝑓: 0.50 (177347 hom.)
• Consequence: FLT4 NM_182925.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.456
• Publications: 4 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=-0.81).
• BP6: Variant 5-180628864-G-A is Benign according to our data. Variant chr5-180628864-G-A is described in ClinVar as Benign. ClinVar VariationId is 263016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLT4	NM_182925.5	c.1103+18C>T		intron_variant	Intron 8 of 29	ENST00000261937.11	NP_891555.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLT4	ENST00000261937.11	c.1103+18C>T		intron_variant	Intron 8 of 29	1	NM_182925.5	ENSP00000261937.6

Frequencies

GnomAD3 genomes AF: 0.481 AC: 72806 AN: 151478 Hom.: 17637 Cov.: 31

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.609

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.466

Gnomad EAS AF: 0.327

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.442

Gnomad NFE AF: 0.507

Gnomad OTH AF: 0.503

GnomAD2 exomes AF: 0.471 AC: 107476 AN: 228020 AF XY: 0.468

Gnomad AFR exome AF: 0.429

Gnomad AMR exome AF: 0.562

Gnomad ASJ exome AF: 0.451

Gnomad EAS exome AF: 0.303

Gnomad FIN exome AF: 0.433

Gnomad NFE exome AF: 0.495

Gnomad OTH exome AF: 0.482

GnomAD4 exome AF: 0.502 AC: 700164 AN: 1393714 Hom.: 177347 Cov.: 25 AF XY: 0.499 AC XY: 347295 AN XY: 695854

African (AFR) AF: 0.438 AC: 14153 AN: 32304

American (AMR) AF: 0.568 AC: 24966 AN: 43916

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 11497 AN: 24878

East Asian (EAS) AF: 0.335 AC: 13055 AN: 38952

South Asian (SAS) AF: 0.435 AC: 36267 AN: 83320

European-Finnish (FIN) AF: 0.453 AC: 20780 AN: 45908

Middle Eastern (MID) AF: 0.465 AC: 2263 AN: 4862

European-Non Finnish (NFE) AF: 0.517 AC: 548868 AN: 1061448

Other (OTH) AF: 0.487 AC: 28315 AN: 58126

GnomAD4 genome AF: 0.480 AC: 72836 AN: 151592 Hom.: 17641 Cov.: 31 AF XY: 0.475 AC XY: 35167 AN XY: 74056

African (AFR) AF: 0.443 AC: 18314 AN: 41330

American (AMR) AF: 0.543 AC: 8279 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.466 AC: 1613 AN: 3462

East Asian (EAS) AF: 0.326 AC: 1678 AN: 5146

South Asian (SAS) AF: 0.453 AC: 2175 AN: 4802

European-Finnish (FIN) AF: 0.446 AC: 4711 AN: 10564

Middle Eastern (MID) AF: 0.428 AC: 124 AN: 290

European-Non Finnish (NFE) AF: 0.507 AC: 34338 AN: 67742

Other (OTH) AF: 0.498 AC: 1051 AN: 2110

Alfa AF: 0.478 Hom.: 3188

Bravo AF: 0.489

ClinVar

Significance: Benign

Submissions summary: Benign:4

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

- -

Congenital heart defects, multiple types, 7 Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary lymphedema type I Benign:1

Aug 10, 2021

Genome-Nilou Lab

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	-0.81
CADD	Benign	13
DANN	Benign	0.70
PhyloP100		0.46
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs438464; hg19: chr5-180055864; COSMIC: COSV56097736; COSMIC: COSV56097736;