4-1024917-C-T

Variant names:

• chr4-1024917-C-T
• NM_001004356.3:c.1085C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001004356.3(FGFRL1):​c.1085C>T​(p.Pro362Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,088 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P362Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FGFRL1 NM_001004356.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.28

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFRL1	NM_001004356.3	c.1085C>T	p.Pro362Leu	missense_variant	Exon 7 of 7	ENST00000510644.6	NP_001004356.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFRL1	ENST00000510644.6	c.1085C>T	p.Pro362Leu	missense_variant	Exon 7 of 7	1	NM_001004356.3	ENSP00000425025.1
FGFRL1	ENST00000264748.6	c.1085C>T	p.Pro362Leu	missense_variant	Exon 6 of 6	1		ENSP00000264748.6
FGFRL1	ENST00000504138.5	c.1085C>T	p.Pro362Leu	missense_variant	Exon 7 of 7	1		ENSP00000423091.1
FGFRL1	ENST00000398484.6	c.1085C>T	p.Pro362Leu	missense_variant	Exon 8 of 8	5		ENSP00000381498.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440088 Hom.: 0 Cov.: 42 AF XY: 0.00000140 AC XY: 1 AN XY: 715124

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;T;T;T
Eigen	Benign	-0.051
Eigen_PC	Benign	-0.0025
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	.;.;.;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Uncertain	0.59	D;D;D;D
MetaSVM	Uncertain	0.089	D
MutationAssessor	Uncertain	2.1	M;M;M;M
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.8	D;D;D;D
REVEL	Uncertain	0.30
Sift	Benign	0.061	T;T;T;T
Sift4G	Uncertain	0.056	T;T;T;T
Polyphen		0.39	B;B;B;B
Vest4		0.18
MutPred		0.38		Loss of glycosylation at P362 (P = 0.0023);Loss of glycosylation at P362 (P = 0.0023);Loss of glycosylation at P362 (P = 0.0023);Loss of glycosylation at P362 (P = 0.0023);
MVP		0.62
MPC		0.15
ClinPred		0.82	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.12
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-1018705;