4-1024711-G-C

Variant names:

• chr4-1024711-G-C
• rs4647944
• NM_001004356.3:c.1072+47G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001004356.3(FGFRL1):​c.1072+47G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,371,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: FGFRL1 NM_001004356.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.94
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFRL1	NM_001004356.3	c.1072+47G>C		intron_variant	Intron 6 of 6	ENST00000510644.6	NP_001004356.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFRL1	ENST00000510644.6	c.1072+47G>C		intron_variant	Intron 6 of 6	1	NM_001004356.3	ENSP00000425025.1
FGFRL1	ENST00000264748.6	c.1072+47G>C		intron_variant	Intron 5 of 5	1		ENSP00000264748.6
FGFRL1	ENST00000504138.5	c.1072+47G>C		intron_variant	Intron 6 of 6	1		ENSP00000423091.1
FGFRL1	ENST00000398484.6	c.1072+47G>C		intron_variant	Intron 7 of 7	5		ENSP00000381498.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1371692 Hom.: 0 Cov.: 29 AF XY: 0.00000148 AC XY: 1 AN XY: 675896

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000316 AC: 1 AN: 31638

American (AMR) AF: 0.00 AC: 0 AN: 38092

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22222

East Asian (EAS) AF: 0.00 AC: 0 AN: 38664

South Asian (SAS) AF: 0.00 AC: 0 AN: 76216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5442

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1064006

Other (OTH) AF: 0.0000176 AC: 1 AN: 56974

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.045
DANN	Benign	0.27
PhyloP100		-2.9

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: rs4647944; hg19: chr4-1018499;