4-1012514-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001004356.3(FGFRL1):ā€‹c.29T>Cā€‹(p.Leu10Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 34)
Exomes š‘“: 7.1e-7 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

FGFRL1
NM_001004356.3 missense

Scores

2
1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.636
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.26661712).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FGFRL1NM_001004356.3 linkuse as main transcriptc.29T>C p.Leu10Pro missense_variant 2/7 ENST00000510644.6 NP_001004356.1 Q8N441A0PJ49

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FGFRL1ENST00000510644.6 linkuse as main transcriptc.29T>C p.Leu10Pro missense_variant 2/71 NM_001004356.3 ENSP00000425025.1 Q8N441

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
7.12e-7
AC:
1
AN:
1403930
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
697202
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000253
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 25, 2024The c.29T>C (p.L10P) alteration is located in exon 2 (coding exon 1) of the FGFRL1 gene. This alteration results from a T to C substitution at nucleotide position 29, causing the leucine (L) at amino acid position 10 to be replaced by a proline (P). 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
0.20
BayesDel_addAF
Benign
0.0060
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
18
DANN
Benign
0.94
DEOGEN2
Benign
0.17
T;T;T;.;.;T
Eigen
Benign
-0.47
Eigen_PC
Benign
-0.48
FATHMM_MKL
Benign
0.21
N
LIST_S2
Benign
0.27
.;.;.;T;T;T
M_CAP
Pathogenic
0.58
D
MetaRNN
Benign
0.27
T;T;T;T;T;T
MetaSVM
Benign
-0.85
T
MutationAssessor
Benign
0.0
N;N;N;.;.;N
PrimateAI
Pathogenic
0.88
D
PROVEAN
Benign
-1.2
N;N;N;N;N;N
REVEL
Uncertain
0.34
Sift
Benign
0.31
T;T;T;D;D;T
Sift4G
Benign
0.080
T;T;T;T;T;T
Polyphen
0.44
B;B;B;.;.;B
Vest4
0.46
MutPred
0.42
Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);
MVP
0.86
MPC
0.23
ClinPred
0.067
T
GERP RS
0.015
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.42
gMVP
0.62

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-1006302; API