rs4647946

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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

GnomAD2 exomes AF: 0.0389 AC: 9614 AN: 246846 AF XY: 0.0379

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 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

African (AFR) AF: 0.0103 AC: 344 AN: 33476

American (AMR) AF: 0.0215 AC: 961 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0398 AC: 1040 AN: 26104

East Asian (EAS) AF: 0.113 AC: 4498 AN: 39694

South Asian (SAS) AF: 0.0138 AC: 1188 AN: 86248

European-Finnish (FIN) AF: 0.0529 AC: 2753 AN: 52054

Middle Eastern (MID) AF: 0.0270 AC: 156 AN: 5768

European-Non Finnish (NFE) AF: 0.0403 AC: 44858 AN: 1111844

Other (OTH) AF: 0.0434 AC: 2619 AN: 60362

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

African (AFR) AF: 0.0123 AC: 512 AN: 41550

American (AMR) AF: 0.0336 AC: 515 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0467 AC: 162 AN: 3472

East Asian (EAS) AF: 0.117 AC: 604 AN: 5162

South Asian (SAS) AF: 0.0178 AC: 86 AN: 4830

European-Finnish (FIN) AF: 0.0476 AC: 505 AN: 10608

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0391 AC: 2655 AN: 67978

Other (OTH) AF: 0.0597 AC: 126 AN: 2112

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4647946; hg19: chr4-1018271;