13-28306688-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002019.4(FLT1):c.3805C>T(p.Leu1269Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000249 in 1,611,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: FLT1 NM_002019.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.435

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.061145335).
• BS2: High AC in GnomAd at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLT1	NM_002019.4	c.3805C>T	p.Leu1269Phe	missense_variant	29/30	ENST00000282397.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLT1	ENST00000282397.9	c.3805C>T	p.Leu1269Phe	missense_variant	29/30	1	NM_002019.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000597 AC: 15 AN: 251458 Hom.: 0 AF XY: 0.0000662 AC XY: 9 AN XY: 135900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000265 AC: 387 AN: 1459008 Hom.: 0 Cov.: 30 AF XY: 0.000215 AC XY: 156 AN XY: 726016

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: 0.000343

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74322

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000262 Hom.: 0

Bravo AF: 0.000102

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.000119

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

Jul 13, 2022

The c.3805C>T (p.L1269F) alteration is located in exon 29 (coding exon 29) of the FLT1 gene. This alteration results from a C to T substitution at nucleotide position 3805, causing the leucine (L) at amino acid position 1269 to be replaced by a phenylalanine (F). 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	Benign	0.077
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	9.2
Dann	Benign	0.72
DEOGEN2	Benign	0.22	T;.;.;.;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.76	T;T;T;T;.
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.061	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.8	L;.;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.59	N;.;.;N;.
REVEL	Benign	0.19
Sift	Benign	0.72	T;.;.;T;.
Sift4G	Benign	0.73	T;D;T;T;D
Polyphen		0.0090	B;.;.;.;.
Vest4		0.17
MVP		0.13
MPC		0.31
ClinPred		0.037	T
GERP RS		3.7
Varity_R		0.027
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs139333864; hg19: chr13-28880825; COSMIC: COSV99149993;