13-28317595-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002019.4(FLT1):c.3289G>A(p.Gly1097Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FLT1 NM_002019.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

Genes affected

FLT1 (HGNC:3763): (fms related receptor tyrosine kinase 1) This gene encodes a member of the vascular endothelial growth factor receptor (VEGFR) family. VEGFR family members are receptor tyrosine kinases (RTKs) which contain an extracellular ligand-binding region with seven immunoglobulin (Ig)-like domains, a transmembrane segment, and a tyrosine kinase (TK) domain within the cytoplasmic domain. This protein binds to VEGFR-A, VEGFR-B and placental growth factor and plays an important role in angiogenesis and vasculogenesis. Expression of this receptor is found in vascular endothelial cells, placental trophoblast cells and peripheral blood monocytes. Multiple transcript variants encoding different isoforms have been found for this gene. Isoforms include a full-length transmembrane receptor isoform and shortened, soluble isoforms. The soluble isoforms are associated with the onset of pre-eclampsia.[provided by RefSeq, May 2009]

LOC124903141 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLT1	NM_002019.4	c.3289G>A	p.Gly1097Arg	missense_variant, splice_region_variant	25/30	ENST00000282397.9
LOC124903141	XR_007063736.1	n.262-934C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLT1	ENST00000282397.9	c.3289G>A	p.Gly1097Arg	missense_variant, splice_region_variant	25/30	1	NM_002019.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456634 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 725048

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2024

The c.3289G>A (p.G1097R) alteration is located in exon 25 (coding exon 25) of the FLT1 gene. This alteration results from a G to A substitution at nucleotide position 3289, causing the glycine (G) at amino acid position 1097 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
Cadd	Benign	23
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.53	D;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.54	T;T;T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Uncertain	0.093	D
MutationAssessor	Benign	0.13	N;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.7	N;.;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.40
MutPred		0.47		Loss of catalytic residue at S1098 (P = 0.0572);.;.;
MVP		0.19
MPC		1.0
ClinPred		0.93	D
GERP RS		6.0
Varity_R		0.71
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs373615531; hg19: chr13-28891732;