4-1025103-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001004356.3(FGFRL1):c.1271G>T(p.Arg424Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,610,698 control chromosomes in the GnomAD database, including 486 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 31 hom., cov: 34)

Exomes 𝑓: 0.022 ( 455 hom. )

Consequence

FGFRL1
NM_001004356.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.83

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=0.0067801178).

BP6

Variant 4-1025103-G-T is Benign according to our data. Variant chr4-1025103-G-T is described in ClinVar as [Benign]. Clinvar id is 1170311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0174 (2656/152274) while in subpopulation NFE AF= 0.0243 (1653/67996). AF 95% confidence interval is 0.0233. There are 31 homozygotes in gnomad4. There are 1377 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFRL1	NM_001004356.3 link	c.1271G>T	p.Arg424Leu	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.1271G>T	p.Arg424Leu	missense_variant	Exon 7 of 7	1	NM_001004356.3	ENSP00000425025.1	Q8N441
FGFRL1	ENST00000264748.6 link	c.1271G>T	p.Arg424Leu	missense_variant	Exon 6 of 6	1		ENSP00000264748.6	Q8N441
FGFRL1	ENST00000504138.5 link	c.1271G>T	p.Arg424Leu	missense_variant	Exon 7 of 7	1		ENSP00000423091.1	Q8N441
FGFRL1	ENST00000398484.6 link	c.1271G>T	p.Arg424Leu	missense_variant	Exon 8 of 8	5		ENSP00000381498.2	Q8N441

Frequencies

GnomAD3 genomes

AF:

0.0175

AC:

2656

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00480

Gnomad AMI

AF:

0.0702

Gnomad AMR

AF:

0.0158

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.0401

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0243

Gnomad OTH

AF:

0.0191

GnomAD3 exomes

AF:

0.0183

AC:

4338

AN:

236502

Hom.:

AF XY:

0.0186

AC XY:

2420

AN XY:

129858

show subpopulations

Gnomad AFR exome

AF:

0.00534

Gnomad AMR exome

AF:

0.0110

Gnomad ASJ exome

AF:

0.00380

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00185

Gnomad FIN exome

AF:

0.0426

Gnomad NFE exome

AF:

0.0267

Gnomad OTH exome

AF:

0.0222

GnomAD4 exome

AF:

0.0221

AC:

32167

AN:

1458424

Hom.:

455

Cov.:

AF XY:

0.0216

AC XY:

15670

AN XY:

725412

show subpopulations

Gnomad4 AFR exome

AF:

0.00392

Gnomad4 AMR exome

AF:

0.0116

Gnomad4 ASJ exome

AF:

0.00422

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00208

Gnomad4 FIN exome

AF:

0.0397

Gnomad4 NFE exome

AF:

0.0250

Gnomad4 OTH exome

AF:

0.0211

GnomAD4 genome

AF:

0.0174

AC:

2656

AN:

152274

Hom.:

Cov.:

AF XY:

0.0185

AC XY:

1377

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00479

Gnomad4 AMR

AF:

0.0158

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.0401

Gnomad4 NFE

AF:

0.0243

Gnomad4 OTH

AF:

0.0189

Alfa

AF:

0.0165

Hom.:

Bravo

AF:

0.0161

TwinsUK

AF:

0.0154

AC:

ALSPAC

AF:

0.0249

AC:

ESP6500AA

AF:

0.00689

AC:

ESP6500EA

AF:

0.0263

AC:

223

ExAC

AF:

0.0178

AC:

2130

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2025	- -

FGFRL1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 06, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;T;T;T

Eigen

Benign

0.079

Eigen_PC

Benign

-0.034

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.77

.;.;.;T

MetaRNN

Benign

0.0068

T;T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.8

L;L;L;L

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.2

N;N;N;N

REVEL

Uncertain

0.31

Sift

Uncertain

0.0070

D;D;D;D

Sift4G

Benign

0.42

T;T;T;T

Polyphen

1.0

D;D;D;D

Vest4

0.12

MPC

0.68

ClinPred

0.017

GERP RS

3.5

Varity_R

0.17

gMVP

0.66

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