4-1023731-G-C

Variant names:

• chr4-1023731-G-C
• rs4647933
• NM_001004356.3:c.433+10G>C

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.433+10G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0401 in 1,558,602 control chromosomes in the GnomAD database, including 1,540 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (134 hom., cov: 31)
  • Exomes 𝑓: 0.041 (1406 hom.)
• Consequence: FGFRL1 NM_001004356.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.406
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 4-1023731-G-C is Benign according to our data. Variant chr4-1023731-G-C is described in ClinVar as Benign. ClinVar VariationId is 1170809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.111 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFRL1	NM_001004356.3	MANE Select	c.433+10G>C		intron	N/A	NP_001004356.1
	FGFRL1	NM_001004358.1		c.433+10G>C		intron	N/A	NP_001004358.1
	FGFRL1	NM_001370296.1		c.433+10G>C		intron	N/A	NP_001357225.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFRL1	ENST00000510644.6	TSL:1 MANE Select	c.433+10G>C		intron	N/A	ENSP00000425025.1
	FGFRL1	ENST00000264748.6	TSL:1	c.433+10G>C		intron	N/A	ENSP00000264748.6
	FGFRL1	ENST00000504138.5	TSL:1	c.433+10G>C		intron	N/A	ENSP00000423091.1

Frequencies

GnomAD3 genomes AF: 0.0342 AC: 5197 AN: 152034 Hom.: 132 Cov.: 31

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0342

Gnomad ASJ AF: 0.0466

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.0476

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0391

Gnomad OTH AF: 0.0531

GnomAD2 exomes AF: 0.0478 AC: 7735 AN: 161912 AF XY: 0.0466

Gnomad AFR exome AF: 0.0143

Gnomad AMR exome AF: 0.0231

Gnomad ASJ exome AF: 0.0490

Gnomad EAS exome AF: 0.136

Gnomad FIN exome AF: 0.0570

Gnomad NFE exome AF: 0.0522

Gnomad OTH exome AF: 0.0462

GnomAD4 exome AF: 0.0407 AC: 57263 AN: 1406452 Hom.: 1406 Cov.: 46 AF XY: 0.0402 AC XY: 27914 AN XY: 694356

African (AFR) AF: 0.0113 AC: 368 AN: 32570

American (AMR) AF: 0.0232 AC: 867 AN: 37368

Ashkenazi Jewish (ASJ) AF: 0.0408 AC: 990 AN: 24284

East Asian (EAS) AF: 0.116 AC: 4390 AN: 37904

South Asian (SAS) AF: 0.0141 AC: 1111 AN: 79004

European-Finnish (FIN) AF: 0.0544 AC: 2617 AN: 48070

Middle Eastern (MID) AF: 0.0311 AC: 133 AN: 4276

European-Non Finnish (NFE) AF: 0.0408 AC: 44214 AN: 1084830

Other (OTH) AF: 0.0443 AC: 2573 AN: 58146

GnomAD4 genome AF: 0.0343 AC: 5212 AN: 152150 Hom.: 134 Cov.: 31 AF XY: 0.0344 AC XY: 2556 AN XY: 74374

African (AFR) AF: 0.0129 AC: 537 AN: 41544

American (AMR) AF: 0.0342 AC: 523 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0466 AC: 161 AN: 3454

East Asian (EAS) AF: 0.119 AC: 610 AN: 5140

South Asian (SAS) AF: 0.0174 AC: 84 AN: 4824

European-Finnish (FIN) AF: 0.0476 AC: 505 AN: 10616

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0391 AC: 2656 AN: 67954

Other (OTH) AF: 0.0578 AC: 122 AN: 2112

Alfa AF: 0.0341 Hom.: 12

Bravo AF: 0.0338

Asia WGS AF: 0.0810 AC: 282 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FGFRL1-related disorder Benign:1

Feb 23, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.7
DANN	Benign	0.79
PhyloP100		-0.41
Mutation Taster		=100/0	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: rs4647933; hg19: chr4-1017519;