rs4647930

Variant names:

• chr4-1024917-C-A
• rs4647930
• NM_001004356.3:c.1085C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-1024917-C-A
• chr4-1024917-C-G
• chr4-1024917-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001004356.3(FGFRL1):​c.1085C>A​(p.Pro362Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,591,946 control chromosomes in the GnomAD database, including 53,995 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3520 hom., cov: 33)
  • Exomes 𝑓: 0.26 (50475 hom.)
• Consequence: FGFRL1 NM_001004356.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.28
• Publications: 33 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=0.0015857816).
• BP6: Variant 4-1024917-C-A is Benign according to our data. Variant chr4-1024917-C-A is described in ClinVar as Benign. ClinVar VariationId is 1164138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

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.1085C>A	p.Pro362Gln	missense	Exon 7 of 7	NP_001004356.1	Q8N441
	FGFRL1	NM_001004358.1		c.1085C>A	p.Pro362Gln	missense	Exon 7 of 7	NP_001004358.1	Q8N441
	FGFRL1	NM_001370296.1		c.1085C>A	p.Pro362Gln	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.1085C>A	p.Pro362Gln	missense	Exon 7 of 7	ENSP00000425025.1	Q8N441
	FGFRL1	ENST00000264748.6	TSL:1	c.1085C>A	p.Pro362Gln	missense	Exon 6 of 6	ENSP00000264748.6	Q8N441
	FGFRL1	ENST00000504138.5	TSL:1	c.1085C>A	p.Pro362Gln	missense	Exon 7 of 7	ENSP00000423091.1	Q8N441

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29382 AN: 152000 Hom.: 3523 Cov.: 33

Gnomad AFR AF: 0.0631

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.0814

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.268

Gnomad OTH AF: 0.216

GnomAD2 exomes AF: 0.220 AC: 51836 AN: 235146 AF XY: 0.228

Gnomad AFR exome AF: 0.0622

Gnomad AMR exome AF: 0.138

Gnomad ASJ exome AF: 0.360

Gnomad EAS exome AF: 0.0836

Gnomad FIN exome AF: 0.230

Gnomad NFE exome AF: 0.275

Gnomad OTH exome AF: 0.261

GnomAD4 exome AF: 0.258 AC: 371823 AN: 1439828 Hom.: 50475 Cov.: 42 AF XY: 0.258 AC XY: 184817 AN XY: 715000

African (AFR) AF: 0.0603 AC: 1992 AN: 33028

American (AMR) AF: 0.143 AC: 6228 AN: 43592

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 9279 AN: 25714

East Asian (EAS) AF: 0.0879 AC: 3462 AN: 39400

South Asian (SAS) AF: 0.220 AC: 18816 AN: 85622

European-Finnish (FIN) AF: 0.232 AC: 10280 AN: 44240

Middle Eastern (MID) AF: 0.295 AC: 1263 AN: 4284

European-Non Finnish (NFE) AF: 0.276 AC: 305365 AN: 1104436

Other (OTH) AF: 0.254 AC: 15138 AN: 59512

GnomAD4 genome AF: 0.193 AC: 29379 AN: 152118 Hom.: 3520 Cov.: 33 AF XY: 0.192 AC XY: 14257 AN XY: 74352

African (AFR) AF: 0.0629 AC: 2613 AN: 41532

American (AMR) AF: 0.177 AC: 2703 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 1243 AN: 3472

East Asian (EAS) AF: 0.0812 AC: 420 AN: 5170

South Asian (SAS) AF: 0.203 AC: 977 AN: 4814

European-Finnish (FIN) AF: 0.232 AC: 2466 AN: 10616

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.268 AC: 18176 AN: 67902

Other (OTH) AF: 0.216 AC: 454 AN: 2106

Alfa AF: 0.232 Hom.: 7500

Bravo AF: 0.182

TwinsUK AF: 0.281 AC: 1043

ALSPAC AF: 0.278 AC: 1072

ESP6500AA AF: 0.0742 AC: 326

ESP6500EA AF: 0.270 AC: 2315

ExAC AF: 0.220 AC: 26631

Asia WGS AF: 0.179 AC: 622 AN: 3476

EpiCase AF: 0.272

EpiControl AF: 0.276

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.31
Sift	Benign	0.14	T
Sift4G	Benign	0.21	T
Polyphen		0.10	B
Vest4		0.19
MPC		0.16
ClinPred		0.010	T
GERP RS		3.9
Varity_R		0.073
gMVP		0.46
Mutation Taster		=98/2	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: rs4647930; hg19: chr4-1018705; COSMIC: COSV53256389; COSMIC: COSV53256389;