4-1025103-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R424C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.017 (31 hom., cov: 34)
  • Exomes 𝑓: 0.022 (455 hom.)
• Consequence: FGFRL1 NM_001004356.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.83

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]

ACMG classification

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 GnomAd at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFRL1	NM_001004356.3	c.1271G>T	p.Arg424Leu	missense_variant	7/7	ENST00000510644.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFRL1	ENST00000510644.6	c.1271G>T	p.Arg424Leu	missense_variant	7/7	1	NM_001004356.3	P1
FGFRL1	ENST00000264748.6	c.1271G>T	p.Arg424Leu	missense_variant	6/6	1		P1
FGFRL1	ENST00000504138.5	c.1271G>T	p.Arg424Leu	missense_variant	7/7	1		P1
FGFRL1	ENST00000398484.6	c.1271G>T	p.Arg424Leu	missense_variant	8/8	5		P1

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2656 AN: 152156 Hom.: 31 Cov.: 34

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.: 65 AF XY: 0.0186 AC XY: 2420 AN XY: 129858

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.: 38 AF XY: 0.0216 AC XY: 15670 AN XY: 725412

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.: 31 Cov.: 34 AF XY: 0.0185 AC XY: 1377 AN XY: 74460

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.: 12

Bravo AF: 0.0161

TwinsUK AF: 0.0154 AC: 57

ALSPAC AF: 0.0249 AC: 96

ESP6500AA AF: 0.00689 AC: 30

ESP6500EA AF: 0.0263 AC: 223

ExAC AF: 0.0178 AC: 2130

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

FGFRL1-related disorder Benign:1

Benign, criteria provided, single submitter

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	24
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	D
MetaRNN	Benign	0.0068	T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.8	L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
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	T
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

Other links and lift over

dbSNP: rs4647931; hg19: chr4-1018891; COSMIC: COSV99063353; COSMIC: COSV99063353;