Genetic Variant NM_001004356.3:c.52G>T (chr4-1012537-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_001004356.3(FGFRL1):c.52G>T(p.Ala18Ser) 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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FGFRL1
NM_001004356.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.845

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:

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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=0.1206103).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFRL1	NM_001004356.3 link	c.52G>T	p.Ala18Ser	missense_variant	Exon 2 of 7	ENST00000510644.6	NP_001004356.1	Q8N441A0PJ49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFRL1	ENST00000510644.6 link	c.52G>T	p.Ala18Ser	missense_variant	Exon 2 of 7	1	NM_001004356.3	ENSP00000425025.1		Q8N441

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1366654

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

677204

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.069

T;T;T;.;.;T

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.36

.;.;.;T;T;T

M_CAP

Pathogenic

0.64

MetaRNN

Benign

0.12

T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.69

N;N;N;.;.;N

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.12

N;N;N;N;N;N

REVEL

Benign

0.031

Sift

Benign

0.074

T;T;T;T;T;T

Sift4G

Benign

0.19

T;T;T;T;T;T

Polyphen

0.012

B;B;B;.;.;B

Vest4

0.16

MutPred

0.36

Gain of sheet (P = 4e-04);Gain of sheet (P = 4e-04);Gain of sheet (P = 4e-04);Gain of sheet (P = 4e-04);Gain of sheet (P = 4e-04);Gain of sheet (P = 4e-04);

MVP

0.34

MPC

0.13

ClinPred

0.064

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.046

gMVP

0.41

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over