4-1022236-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001004356.3(FGFRL1):c.113G>A(p.Arg38Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000323 in 1,554,480 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. R38R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00034 (7 hom.)
• Consequence: FGFRL1 NM_001004356.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.02

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009086192).
• BP6: Variant 4-1022236-G-A is Benign according to our data. Variant chr4-1022236-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2421658.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFRL1	NM_001004356.3	c.113G>A	p.Arg38Gln	missense_variant	3/7	ENST00000510644.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFRL1	ENST00000510644.6	c.113G>A	p.Arg38Gln	missense_variant	3/7	1	NM_001004356.3	P1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152118 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00498

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000699 AC: 134 AN: 191774 Hom.: 0 AF XY: 0.000878 AC XY: 93 AN XY: 105890

Gnomad AFR exome AF: 0.0000866

Gnomad AMR exome AF: 0.0000734

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00534

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00108

GnomAD4 exome AF: 0.000340 AC: 477 AN: 1402246 Hom.: 7 Cov.: 31 AF XY: 0.000482 AC XY: 333 AN XY: 690544

Gnomad4 AFR exome AF: 0.0000316

Gnomad4 AMR exome AF: 0.0000517

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00556

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000556

Gnomad4 OTH exome AF: 0.000417

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152234 Hom.: 1 Cov.: 34 AF XY: 0.000242 AC XY: 18 AN XY: 74446

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00519

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.000721 AC: 85

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Apr 25, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.084	T;T;T;.;.;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.52
FATHMM_MKL	Uncertain	0.94	D
MetaRNN	Benign	0.0091	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.42	N;N;N;.;.;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.1	N;N;N;N;N;N
REVEL	Benign	0.061
Sift	Benign	0.30	T;T;T;T;D;T
Sift4G	Benign	0.24	T;T;T;D;T;T
Polyphen		0.22	B;B;B;.;.;B
Vest4		0.42
MutPred		0.43		Loss of MoRF binding (P = 0.0382);Loss of MoRF binding (P = 0.0382);Loss of MoRF binding (P = 0.0382);Loss of MoRF binding (P = 0.0382);Loss of MoRF binding (P = 0.0382);Loss of MoRF binding (P = 0.0382);
MVP		0.45
MPC		0.27
ClinPred		0.058	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.073
gMVP		0.65

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: rs557619683; hg19: chr4-1016024; COSMIC: COSV99294905;