8-17868981-G-A
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_004467.4(FGL1):c.526C>T(p.Leu176Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000312 in 1,601,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000028 ( 0 hom. )
Consequence
FGL1
NM_004467.4 missense
NM_004467.4 missense
Scores
2
9
7
Clinical Significance
Conservation
PhyloP100: 3.09
Genes affected
FGL1 (HGNC:3695): (fibrinogen like 1) Fibrinogen-like 1 is a member of the fibrinogen family. This protein is homologous to the carboxy terminus of the fibrinogen beta- and gamma- subunits which contains the four conserved cysteines of fibrinogens and fibrinogen related proteins. However, this protein lacks the platelet-binding site, cross-linking region and a thrombin-sensitive site which are necessary for fibrin clot formation. This protein may play a role in the development of hepatocellular carcinomas. Four alternatively spliced transcript variants encoding the same protein exist for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.974
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FGL1 | NM_004467.4 | c.526C>T | p.Leu176Phe | missense_variant | 6/8 | ENST00000427924.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FGL1 | ENST00000427924.5 | c.526C>T | p.Leu176Phe | missense_variant | 6/8 | 1 | NM_004467.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000659 AC: 1AN: 151842Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000415 AC: 1AN: 240924Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 130564
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GnomAD4 exome AF: 0.00000276 AC: 4AN: 1449312Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1AN XY: 720712
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GnomAD4 genome AF: 0.00000659 AC: 1AN: 151842Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74134
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 03, 2022 | The c.526C>T (p.L176F) alteration is located in exon 7 (coding exon 5) of the FGL1 gene. This alteration results from a C to T substitution at nucleotide position 526, causing the leucine (L) at amino acid position 176 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Benign
T;T;T;T;T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;M;M;M;M;M
MutationTaster
Benign
D;D;D;D;D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D
Polyphen
D;D;D;D;D;D;D
Vest4
MutPred
Loss of ubiquitination at K181 (P = 0.1216);Loss of ubiquitination at K181 (P = 0.1216);Loss of ubiquitination at K181 (P = 0.1216);Loss of ubiquitination at K181 (P = 0.1216);Loss of ubiquitination at K181 (P = 0.1216);Loss of ubiquitination at K181 (P = 0.1216);Loss of ubiquitination at K181 (P = 0.1216);
MVP
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at