4-1022218-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001004356.3(FGFRL1):c.95C>T(p.Ala32Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000768 in 1,535,486 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A32A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0040 (5 hom., cov: 34)
  • Exomes 𝑓: 0.00041 (5 hom.)
• Consequence: FGFRL1 NM_001004356.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.32

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077757537).
• BP6: Variant 4-1022218-C-T is Benign according to our data. Variant chr4-1022218-C-T is described in ClinVar as [Benign]. Clinvar id is 710923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFRL1	NM_001004356.3	c.95C>T	p.Ala32Val	missense_variant	3/7	ENST00000510644.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFRL1	ENST00000510644.6	c.95C>T	p.Ala32Val	missense_variant	3/7	1	NM_001004356.3	P1

Frequencies

GnomAD3 genomes AF: 0.00399 AC: 608 AN: 152214 Hom.: 5 Cov.: 34

Gnomad AFR AF: 0.0142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000984 AC: 177 AN: 179966 Hom.: 2 AF XY: 0.000729 AC XY: 72 AN XY: 98812

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.000663

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000372

Gnomad OTH exome AF: 0.000951

GnomAD4 exome AF: 0.000412 AC: 570 AN: 1383154 Hom.: 5 Cov.: 31 AF XY: 0.000364 AC XY: 247 AN XY: 679068

Gnomad4 AFR exome AF: 0.0155

Gnomad4 AMR exome AF: 0.000659

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000132

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000187

Gnomad4 OTH exome AF: 0.000670

GnomAD4 genome AF: 0.00400 AC: 610 AN: 152332 Hom.: 5 Cov.: 34 AF XY: 0.00366 AC XY: 273 AN XY: 74496

Gnomad4 AFR AF: 0.0142

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000617 Hom.: 0

Bravo AF: 0.00447

ESP6500AA AF: 0.0124 AC: 48

ESP6500EA AF: 0.000380 AC: 3

ExAC AF: 0.00110 AC: 130

Asia WGS AF: 0.00115 AC: 4 AN: 3478

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

Mar 22, 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 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T;T;.;.;T
Eigen	Benign	0.065
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.0078	T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-0.43	N;N;N;.;.;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.5	N;N;N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.17	T;T;T;D;D;T
Sift4G	Uncertain	0.019	D;D;D;D;D;D
Polyphen		0.97	D;D;D;.;.;D
Vest4		0.42
MVP		0.52
MPC		0.47
ClinPred		0.032	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.091
gMVP		0.34

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: rs78299800; hg19: chr4-1016006;