5-180628862-T-G

Variant names:

• chr5-180628862-T-G
• rs383985
• NM_182925.5:c.1103+20A>C

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+20A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.582 in 1,535,060 control chromosomes in the GnomAD database, including 262,661 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (25376 hom., cov: 31)
  • Exomes 𝑓: 0.58 (237285 hom.)
• Consequence: FLT4 NM_182925.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.07
• Publications: 13 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=-0.97).
• BP6: Variant 5-180628862-T-G is Benign according to our data. Variant chr5-180628862-T-G is described in ClinVar as Benign. ClinVar VariationId is 263017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLT4	NM_182925.5	c.1103+20A>C		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+20A>C		intron_variant	Intron 8 of 29	1	NM_182925.5	ENSP00000261937.6

Frequencies

GnomAD3 genomes AF: 0.575 AC: 87092 AN: 151350 Hom.: 25338 Cov.: 31

Gnomad AFR AF: 0.550

Gnomad AMI AF: 0.651

Gnomad AMR AF: 0.653

Gnomad ASJ AF: 0.550

Gnomad EAS AF: 0.814

Gnomad SAS AF: 0.596

Gnomad FIN AF: 0.511

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.564

Gnomad OTH AF: 0.596

GnomAD2 exomes AF: 0.613 AC: 138649 AN: 226054 AF XY: 0.605

Gnomad AFR exome AF: 0.541

Gnomad AMR exome AF: 0.734

Gnomad ASJ exome AF: 0.565

Gnomad EAS exome AF: 0.823

Gnomad FIN exome AF: 0.533

Gnomad NFE exome AF: 0.572

Gnomad OTH exome AF: 0.587

GnomAD4 exome AF: 0.583 AC: 806235 AN: 1383594 Hom.: 237285 Cov.: 23 AF XY: 0.581 AC XY: 401645 AN XY: 691210

African (AFR) AF: 0.542 AC: 17389 AN: 32102

American (AMR) AF: 0.728 AC: 32207 AN: 44214

Ashkenazi Jewish (ASJ) AF: 0.562 AC: 13869 AN: 24680

East Asian (EAS) AF: 0.788 AC: 30826 AN: 39114

South Asian (SAS) AF: 0.573 AC: 47522 AN: 82940

European-Finnish (FIN) AF: 0.523 AC: 23668 AN: 45268

Middle Eastern (MID) AF: 0.604 AC: 2754 AN: 4560

European-Non Finnish (NFE) AF: 0.574 AC: 604346 AN: 1052954

Other (OTH) AF: 0.583 AC: 33654 AN: 57762

GnomAD4 genome AF: 0.576 AC: 87178 AN: 151466 Hom.: 25376 Cov.: 31 AF XY: 0.574 AC XY: 42491 AN XY: 73988

African (AFR) AF: 0.550 AC: 22701 AN: 41274

American (AMR) AF: 0.654 AC: 9957 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 1906 AN: 3464

East Asian (EAS) AF: 0.814 AC: 4165 AN: 5118

South Asian (SAS) AF: 0.597 AC: 2872 AN: 4808

European-Finnish (FIN) AF: 0.511 AC: 5386 AN: 10536

Middle Eastern (MID) AF: 0.528 AC: 153 AN: 290

European-Non Finnish (NFE) AF: 0.564 AC: 38187 AN: 67724

Other (OTH) AF: 0.598 AC: 1260 AN: 2108

Alfa AF: 0.477 Hom.: 1932

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

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	-0.97
CADD	Benign	1.2
DANN	Benign	0.13
PhyloP100		-4.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs383985; hg19: chr5-180055862;