4-1023961-G-C

Variant names:

• chr4-1023961-G-C
• rs4647937
• NM_001004356.3:c.578G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001004356.3(FGFRL1):​c.578G>C​(p.Arg193Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,443,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R193C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FGFRL1 NM_001004356.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92
• Publications: 3 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08507663).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004356.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFRL1	NM_001004356.3	MANE Select	c.578G>C	p.Arg193Pro	missense	Exon 5 of 7	NP_001004356.1
	FGFRL1	NM_001004358.1		c.578G>C	p.Arg193Pro	missense	Exon 5 of 7	NP_001004358.1
	FGFRL1	NM_001370296.1		c.578G>C	p.Arg193Pro	missense	Exon 5 of 7	NP_001357225.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFRL1	ENST00000510644.6	TSL:1 MANE Select	c.578G>C	p.Arg193Pro	missense	Exon 5 of 7	ENSP00000425025.1
	FGFRL1	ENST00000264748.6	TSL:1	c.578G>C	p.Arg193Pro	missense	Exon 4 of 6	ENSP00000264748.6
	FGFRL1	ENST00000504138.5	TSL:1	c.578G>C	p.Arg193Pro	missense	Exon 5 of 7	ENSP00000423091.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1443610 Hom.: 0 Cov.: 47 AF XY: 0.00000279 AC XY: 2 AN XY: 717472

African (AFR) AF: 0.00 AC: 0 AN: 33024

American (AMR) AF: 0.00 AC: 0 AN: 43086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25858

East Asian (EAS) AF: 0.00 AC: 0 AN: 38620

South Asian (SAS) AF: 0.00 AC: 0 AN: 83898

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1105922

Other (OTH) AF: 0.00 AC: 0 AN: 59756

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.9
DANN	Benign	0.84
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.15	N
PhyloP100		1.9
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.092
Sift	Benign	0.32	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.53		Gain of catalytic residue at R193 (P = 0.0044)
MVP		0.13
MPC		0.21
ClinPred		0.064	T
GERP RS		2.0
Varity_R		0.11
gMVP		0.65
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4647937; hg19: chr4-1017749;