rs4647946

Variant names:

• chr4-1024483-T-C
• rs4647946
• NM_001004356.3:c.891T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001004356.3(FGFRL1):​c.891T>C​(p.Asp297Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0394 in 1,612,472 control chromosomes in the GnomAD database, including 1,546 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (135 hom., cov: 33)
  • Exomes 𝑓: 0.040 (1411 hom.)
• Consequence: FGFRL1 NM_001004356.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.84

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 4-1024483-T-C is Benign according to our data. Variant chr4-1024483-T-C is described in ClinVar as [Benign]. Clinvar id is 1170810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.85 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFRL1	NM_001004356.3	c.891T>C	p.Asp297Asp	synonymous_variant	Exon 6 of 7	ENST00000510644.6	NP_001004356.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFRL1	ENST00000510644.6	c.891T>C	p.Asp297Asp	synonymous_variant	Exon 6 of 7	1	NM_001004356.3	ENSP00000425025.1
FGFRL1	ENST00000264748.6	c.891T>C	p.Asp297Asp	synonymous_variant	Exon 5 of 6	1		ENSP00000264748.6
FGFRL1	ENST00000504138.5	c.891T>C	p.Asp297Asp	synonymous_variant	Exon 6 of 7	1		ENSP00000423091.1
FGFRL1	ENST00000398484.6	c.891T>C	p.Asp297Asp	synonymous_variant	Exon 7 of 8	5		ENSP00000381498.2

Frequencies

GnomAD3 genomes AF: 0.0339 AC: 5162 AN: 152106 Hom.: 132 Cov.: 33

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0337

Gnomad ASJ AF: 0.0467

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.0476

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0391

Gnomad OTH AF: 0.0536

GnomAD3 exomes AF: 0.0389 AC: 9614 AN: 246846 Hom.: 286 AF XY: 0.0379 AC XY: 5097 AN XY: 134334

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.0203

Gnomad ASJ exome AF: 0.0431

Gnomad EAS exome AF: 0.116

Gnomad SAS exome AF: 0.0139

Gnomad FIN exome AF: 0.0515

Gnomad NFE exome AF: 0.0401

Gnomad OTH exome AF: 0.0419

GnomAD4 exome AF: 0.0400 AC: 58417 AN: 1460248 Hom.: 1411 Cov.: 33 AF XY: 0.0394 AC XY: 28631 AN XY: 726442

Gnomad4 AFR exome AF: 0.0103

Gnomad4 AMR exome AF: 0.0215

Gnomad4 ASJ exome AF: 0.0398

Gnomad4 EAS exome AF: 0.113

Gnomad4 SAS exome AF: 0.0138

Gnomad4 FIN exome AF: 0.0529

Gnomad4 NFE exome AF: 0.0403

Gnomad4 OTH exome AF: 0.0434

GnomAD4 genome AF: 0.0340 AC: 5179 AN: 152224 Hom.: 135 Cov.: 33 AF XY: 0.0343 AC XY: 2553 AN XY: 74414

Gnomad4 AFR AF: 0.0123

Gnomad4 AMR AF: 0.0336

Gnomad4 ASJ AF: 0.0467

Gnomad4 EAS AF: 0.117

Gnomad4 SAS AF: 0.0178

Gnomad4 FIN AF: 0.0476

Gnomad4 NFE AF: 0.0391

Gnomad4 OTH AF: 0.0597

Alfa AF: 0.0359 Hom.: 48

Bravo AF: 0.0333

Asia WGS AF: 0.0790 AC: 275 AN: 3478

EpiCase AF: 0.0407

EpiControl AF: 0.0401

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FGFRL1-related disorder Benign:1

Feb 23, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.69
DANN	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs4647946; hg19: chr4-1018271;