rs4647933

Positions:

• chr4-1023731-G-C
• chr4-1023731-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001004356.3(FGFRL1):​c.433+10G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0401 in 1,558,602 control chromosomes in the GnomAD database, including 1,540 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (134 hom., cov: 31)
  • Exomes 𝑓: 0.041 (1406 hom.)
• Consequence: FGFRL1 NM_001004356.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.406

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 (BayesDel_noAF=-0.81).
• BP6: Variant 4-1023731-G-C is Benign according to our data. Variant chr4-1023731-G-C is described in ClinVar as [Benign]. Clinvar id is 1170809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFRL1	NM_001004356.3	c.433+10G>C		intron_variant		ENST00000510644.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFRL1	ENST00000510644.6	c.433+10G>C		intron_variant		1	NM_001004356.3	P1

Frequencies

GnomAD3 genomes AF: 0.0342 AC: 5197 AN: 152034 Hom.: 132 Cov.: 31

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0342

Gnomad ASJ AF: 0.0466

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.0476

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0391

Gnomad OTH AF: 0.0531

GnomAD3 exomes AF: 0.0478 AC: 7735 AN: 161912 Hom.: 258 AF XY: 0.0466 AC XY: 4090 AN XY: 87804

Gnomad AFR exome AF: 0.0143

Gnomad AMR exome AF: 0.0231

Gnomad ASJ exome AF: 0.0490

Gnomad EAS exome AF: 0.136

Gnomad SAS exome AF: 0.0157

Gnomad FIN exome AF: 0.0570

Gnomad NFE exome AF: 0.0522

Gnomad OTH exome AF: 0.0462

GnomAD4 exome AF: 0.0407 AC: 57263 AN: 1406452 Hom.: 1406 Cov.: 46 AF XY: 0.0402 AC XY: 27914 AN XY: 694356

Gnomad4 AFR exome AF: 0.0113

Gnomad4 AMR exome AF: 0.0232

Gnomad4 ASJ exome AF: 0.0408

Gnomad4 EAS exome AF: 0.116

Gnomad4 SAS exome AF: 0.0141

Gnomad4 FIN exome AF: 0.0544

Gnomad4 NFE exome AF: 0.0408

Gnomad4 OTH exome AF: 0.0443

GnomAD4 genome AF: 0.0343 AC: 5212 AN: 152150 Hom.: 134 Cov.: 31 AF XY: 0.0344 AC XY: 2556 AN XY: 74374

Gnomad4 AFR AF: 0.0129

Gnomad4 AMR AF: 0.0342

Gnomad4 ASJ AF: 0.0466

Gnomad4 EAS AF: 0.119

Gnomad4 SAS AF: 0.0174

Gnomad4 FIN AF: 0.0476

Gnomad4 NFE AF: 0.0391

Gnomad4 OTH AF: 0.0578

Alfa AF: 0.0341 Hom.: 12

Bravo AF: 0.0338

Asia WGS AF: 0.0810 AC: 282 AN: 3476

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

Feb 23, 2019

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 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.7
DANN	Benign	0.79

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: rs4647933; hg19: chr4-1017519;