13-28311623-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002019.4(FLT1):c.3602C>T(p.Pro1201Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00403 in 1,613,588 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (16 hom.)
• Consequence: FLT1 NM_002019.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.78

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053360164).
• BP6: Variant 13-28311623-G-A is Benign according to our data. Variant chr13-28311623-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 713553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 433 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLT1	NM_002019.4	c.3602C>T	p.Pro1201Leu	missense_variant	27/30	ENST00000282397.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLT1	ENST00000282397.9	c.3602C>T	p.Pro1201Leu	missense_variant	27/30	1	NM_002019.4	P1

Frequencies

GnomAD3 genomes AF: 0.00285 AC: 433 AN: 151980 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00246

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00465

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00267 AC: 670 AN: 251318 Hom.: 1 AF XY: 0.00246 AC XY: 334 AN XY: 135842

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00933

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00268

Gnomad NFE exome AF: 0.00360

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00416 AC: 6076 AN: 1461490 Hom.: 16 Cov.: 32 AF XY: 0.00400 AC XY: 2906 AN XY: 727070

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00888

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000615

Gnomad4 FIN exome AF: 0.00212

Gnomad4 NFE exome AF: 0.00480

Gnomad4 OTH exome AF: 0.00404

GnomAD4 genome AF: 0.00285 AC: 433 AN: 152098 Hom.: 1 Cov.: 32 AF XY: 0.00262 AC XY: 195 AN XY: 74334

Gnomad4 AFR AF: 0.000747

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00246

Gnomad4 NFE AF: 0.00465

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.00412 Hom.: 1

Bravo AF: 0.00257

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00219 AC: 266

Asia WGS AF: 0.00115 AC: 5 AN: 3478

EpiCase AF: 0.00404

EpiControl AF: 0.00302

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	FLT1: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Apr 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	20
Dann	Benign	0.90
DEOGEN2	Benign	0.39	T;.;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.65	T;T;T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.0053	T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.9	L;.;.
MutationTaster	Benign	0.61	D;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.7	N;.;D
REVEL	Uncertain	0.43
Sift	Benign	0.041	D;.;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.87	P;.;.
Vest4		0.21
MVP		0.37
MPC		0.34
ClinPred		0.055	T
GERP RS		6.0
Varity_R		0.052
gMVP		0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs140861115; hg19: chr13-28885760;