Genetic Variant FGFRL1:c.1072+47G>C (chr4-1024711-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.94

Publications

0 publications found

Variant links:

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]

FGFRL1 links:

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ACMG classification

Classification was made for transcript

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).

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FGFRL1	NM_001004356.3	MANE Select	c.1072+47G>C	intron	N/A	NP_001004356.1	Q8N441
FGFRL1	NM_001004358.1		c.1072+47G>C	intron	N/A	NP_001004358.1	Q8N441
FGFRL1	NM_001370296.1		c.1072+47G>C	intron	N/A	NP_001357225.1	Q8N441

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FGFRL1	ENST00000510644.6	TSL:1 MANE Select	c.1072+47G>C	intron	N/A	ENSP00000425025.1	Q8N441
FGFRL1	ENST00000264748.6	TSL:1	c.1072+47G>C	intron	N/A	ENSP00000264748.6	Q8N441
FGFRL1	ENST00000504138.5	TSL:1	c.1072+47G>C	intron	N/A	ENSP00000423091.1	Q8N441

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000146

AC:

AN:

1371692

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

675896

show subpopulations

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

African (AFR)

AF:

0.0000316

AC:

AN:

31638

American (AMR)

AF:

0.00

AC:

AN:

38092

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22222

East Asian (EAS)

AF:

0.00

AC:

AN:

38664

South Asian (SAS)

AF:

0.00

AC:

AN:

76216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38438

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5442

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1064006

Other (OTH)

AF:

0.0000176

AC:

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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.045

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over