4-1012561-C-G

Position:

chr4-1012561-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001004356.3(FGFRL1):c.76C>G(p.Arg26Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000228 in 1,424,098 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

FGFRL1
NM_001004356.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.187

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15312791).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFRL1	NM_001004356.3 linkuse as main transcript	c.76C>G	p.Arg26Gly	missense_variant	2/7	ENST00000510644.6	NP_001004356.1	Q8N441A0PJ49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFRL1	ENST00000510644.6 linkuse as main transcript	c.76C>G	p.Arg26Gly	missense_variant	2/7	1	NM_001004356.3	ENSP00000425025.1		Q8N441

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000175

AC:

AN:

91572

Hom.:

AF XY:

0.000135

AC XY:

AN XY:

51844

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000108

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000467

Gnomad NFE exome

AF:

0.000331

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000238

AC:

303

AN:

1271852

Hom.:

Cov.:

AF XY:

0.000245

AC XY:

155

AN XY:

631406

show subpopulations

Gnomad4 AFR exome

AF:

0.0000386

Gnomad4 AMR exome

AF:

0.000132

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000305

Gnomad4 NFE exome

AF:

0.000276

Gnomad4 OTH exome

AF:

0.000225

GnomAD4 genome

AF:

0.000145

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000778

Hom.:

Bravo

AF:

0.000204

ExAC

AF:

0.000157

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3472

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.76C>G (p.R26G) alteration is located in exon 2 (coding exon 1) of the FGFRL1 gene. This alteration results from a C to G substitution at nucleotide position 76, causing the arginine (R) at amino acid position 26 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 24, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 1485221). This variant has not been reported in the literature in individuals affected with FGFRL1-related conditions. This variant is present in population databases (rs768315040, gnomAD 0.05%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 26 of the FGFRL1 protein (p.Arg26Gly). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.21

T;T;T;.;.;T

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.51

.;.;.;T;T;T

M_CAP

Pathogenic

0.83

MetaRNN

Benign

0.15

T;T;T;T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.0

L;L;L;.;.;L

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.9

N;N;N;D;N;N

REVEL

Benign

0.14

Sift

Uncertain

0.0070

D;D;D;D;D;D

Sift4G

Uncertain

0.010

D;D;D;D;D;D

Polyphen

0.19

B;B;B;.;.;B

Vest4

0.29

MVP

0.75

MPC

0.18

ClinPred

0.078

GERP RS

1.5

Varity_R

0.17

gMVP

0.42

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