4-1025223-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001004356.3(FGFRL1):c.1391C>T(p.Pro464Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0594 in 1,609,166 control chromosomes in the GnomAD database, including 3,126 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.049 ( 230 hom., cov: 34)

Exomes 𝑓: 0.061 ( 2896 hom. )

Consequence

FGFRL1
NM_001004356.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.63

Variant links:

Genes affected

FGFRL1 (HGNC:3693): (fibroblast growth factor receptor like 1) The protein encoded by this gene is a member of the fibroblast growth factor receptor (FGFR) family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein would consist of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. A marked difference between this gene product and the other family members is its lack of a cytoplasmic tyrosine kinase domain. The result is a transmembrane receptor that could interact with other family members and potentially inhibit signaling. Multiple alternatively spliced transcript variants encoding the same isoform have been found for this gene. [provided by RefSeq, Jul 2008]

FGFRL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016242862).

BP6

Variant 4-1025223-C-T is Benign according to our data. Variant chr4-1025223-C-T is described in ClinVar as [Benign]. Clinvar id is 1169918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFRL1	NM_001004356.3 link	c.1391C>T	p.Pro464Leu	missense_variant	Exon 7 of 7	ENST00000510644.6	NP_001004356.1	Q8N441A0PJ49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FGFRL1	ENST00000510644.6 link	c.1391C>T	p.Pro464Leu	missense_variant	Exon 7 of 7	1	NM_001004356.3	ENSP00000425025.1	Q8N441
FGFRL1	ENST00000264748.6 link	c.1391C>T	p.Pro464Leu	missense_variant	Exon 6 of 6	1		ENSP00000264748.6	Q8N441
FGFRL1	ENST00000504138.5 link	c.1391C>T	p.Pro464Leu	missense_variant	Exon 7 of 7	1		ENSP00000423091.1	Q8N441
FGFRL1	ENST00000398484.6 link	c.1391C>T	p.Pro464Leu	missense_variant	Exon 8 of 8	5		ENSP00000381498.2	Q8N441

Frequencies

GnomAD3 genomes

AF:

0.0488

AC:

7425

AN:

152170

Hom.:

230

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0175

Gnomad AMI

AF:

0.0395

Gnomad AMR

AF:

0.0663

Gnomad ASJ

AF:

0.126

Gnomad EAS

AF:

0.0181

Gnomad SAS

AF:

0.0298

Gnomad FIN

AF:

0.0353

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.0646

Gnomad OTH

AF:

0.0745

GnomAD3 exomes

AF:

0.0534

AC:

12580

AN:

235606

Hom.:

414

AF XY:

0.0535

AC XY:

6918

AN XY:

129232

show subpopulations

Gnomad AFR exome

AF:

0.0153

Gnomad AMR exome

AF:

0.0609

Gnomad ASJ exome

AF:

0.128

Gnomad EAS exome

AF:

0.0168

Gnomad SAS exome

AF:

0.0305

Gnomad FIN exome

AF:

0.0325

Gnomad NFE exome

AF:

0.0648

Gnomad OTH exome

AF:

0.0736

GnomAD4 exome

AF:

0.0606

AC:

88224

AN:

1456878

Hom.:

2896

Cov.:

AF XY:

0.0600

AC XY:

43438

AN XY:

724436

show subpopulations

Gnomad4 AFR exome

AF:

0.0180

Gnomad4 AMR exome

AF:

0.0619

Gnomad4 ASJ exome

AF:

0.128

Gnomad4 EAS exome

AF:

0.0252

Gnomad4 SAS exome

AF:

0.0300

Gnomad4 FIN exome

AF:

0.0343

Gnomad4 NFE exome

AF:

0.0645

Gnomad4 OTH exome

AF:

0.0641

GnomAD4 genome

AF:

0.0488

AC:

7426

AN:

152288

Hom.:

230

Cov.:

AF XY:

0.0472

AC XY:

3516

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0175

Gnomad4 AMR

AF:

0.0665

Gnomad4 ASJ

AF:

0.126

Gnomad4 EAS

AF:

0.0180

Gnomad4 SAS

AF:

0.0296

Gnomad4 FIN

AF:

0.0353

Gnomad4 NFE

AF:

0.0646

Gnomad4 OTH

AF:

0.0751

Alfa

AF:

0.0631

Hom.:

655

Bravo

AF:

0.0501

TwinsUK

AF:

0.0593

AC:

220

ALSPAC

AF:

0.0620

AC:

239

ESP6500AA

AF:

0.0173

AC:

ESP6500EA

AF:

0.0673

AC:

578

ExAC

AF:

0.0509

AC:

6148

Asia WGS

AF:

0.0480

AC:

167

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.60

DEOGEN2

Benign

0.11

T;T;T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.59

.;.;.;T

MetaRNN

Benign

0.0016

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;L;L;L

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.4

N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.050

D;D;D;D

Sift4G

Uncertain

0.0050

D;D;D;D

Polyphen

0.0

B;B;B;B

Vest4

0.020

MPC

0.14

ClinPred

0.0081

GERP RS

1.5

Varity_R

0.024

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over