4-1025103-G-T

Variant names:

• chr4-1025103-G-T
• rs4647931
• NM_001004356.3:c.1271G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001004356.3(FGFRL1):​c.1271G>T​(p.Arg424Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,610,698 control chromosomes in the GnomAD database, including 486 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R424C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.017 (31 hom., cov: 34)
  • Exomes 𝑓: 0.022 (455 hom.)
• Consequence: FGFRL1 NM_001004356.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.83
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067801178).
• BP6: Variant 4-1025103-G-T is Benign according to our data. Variant chr4-1025103-G-T is described in ClinVar as Benign. ClinVar VariationId is 1170311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0174 (2656/152274) while in subpopulation NFE AF = 0.0243 (1653/67996). AF 95% confidence interval is 0.0233. There are 31 homozygotes in GnomAd4. There are 1377 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFRL1	NM_001004356.3	MANE Select	c.1271G>T	p.Arg424Leu	missense	Exon 7 of 7	NP_001004356.1	Q8N441
	FGFRL1	NM_001004358.1		c.1271G>T	p.Arg424Leu	missense	Exon 7 of 7	NP_001004358.1	Q8N441
	FGFRL1	NM_001370296.1		c.1271G>T	p.Arg424Leu	missense	Exon 7 of 7	NP_001357225.1	Q8N441

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFRL1	ENST00000510644.6	TSL:1 MANE Select	c.1271G>T	p.Arg424Leu	missense	Exon 7 of 7	ENSP00000425025.1	Q8N441
	FGFRL1	ENST00000264748.6	TSL:1	c.1271G>T	p.Arg424Leu	missense	Exon 6 of 6	ENSP00000264748.6	Q8N441
	FGFRL1	ENST00000504138.5	TSL:1	c.1271G>T	p.Arg424Leu	missense	Exon 7 of 7	ENSP00000423091.1	Q8N441

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2656 AN: 152156 Hom.: 31 Cov.: 34

Gnomad AFR AF: 0.00480

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0401

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0243

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.0183 AC: 4338 AN: 236502 AF XY: 0.0186

Gnomad AFR exome AF: 0.00534

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.00380

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0426

Gnomad NFE exome AF: 0.0267

Gnomad OTH exome AF: 0.0222

GnomAD4 exome AF: 0.0221 AC: 32167 AN: 1458424 Hom.: 455 Cov.: 38 AF XY: 0.0216 AC XY: 15670 AN XY: 725412

African (AFR) AF: 0.00392 AC: 131 AN: 33438

American (AMR) AF: 0.0116 AC: 517 AN: 44524

Ashkenazi Jewish (ASJ) AF: 0.00422 AC: 110 AN: 26056

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39646

South Asian (SAS) AF: 0.00208 AC: 179 AN: 86060

European-Finnish (FIN) AF: 0.0397 AC: 2057 AN: 51786

Middle Eastern (MID) AF: 0.0155 AC: 89 AN: 5750

European-Non Finnish (NFE) AF: 0.0250 AC: 27812 AN: 1110930

Other (OTH) AF: 0.0211 AC: 1271 AN: 60234

GnomAD4 genome AF: 0.0174 AC: 2656 AN: 152274 Hom.: 31 Cov.: 34 AF XY: 0.0185 AC XY: 1377 AN XY: 74460

African (AFR) AF: 0.00479 AC: 199 AN: 41570

American (AMR) AF: 0.0158 AC: 242 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4822

European-Finnish (FIN) AF: 0.0401 AC: 426 AN: 10620

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0243 AC: 1653 AN: 67996

Other (OTH) AF: 0.0189 AC: 40 AN: 2114

Alfa AF: 0.0165 Hom.: 17

Bravo AF: 0.0161

TwinsUK AF: 0.0154 AC: 57

ALSPAC AF: 0.0249 AC: 96

ESP6500AA AF: 0.00689 AC: 30

ESP6500EA AF: 0.0263 AC: 223

ExAC AF: 0.0178 AC: 2130

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	FGFRL1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.079
Eigen_PC	Benign	-0.034
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.42	T
Polyphen		1.0	D
Vest4		0.12
MPC		0.68
ClinPred		0.017	T
GERP RS		3.5
Varity_R		0.17
gMVP		0.66
Mutation Taster		=99/1	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: rs4647931; hg19: chr4-1018891; COSMIC: COSV99063353; COSMIC: COSV99063353;