Variant chr8-17868981-G-A details in Genebe, Genetics Data Aggregator

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.09

Variant links:

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]

FGL1 links:

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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 linkuse as main transcript	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 linkuse as main transcript	c.526C>T	p.Leu176Phe	missense_variant	6/8	1	NM_004467.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151842

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000415

AC:

AN:

240924

Hom.:

AF XY:

0.00

AC XY:

AN XY:

130564

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000311

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1449312

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720712

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000236

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151842

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74134

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.013

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.057

T;T;T;T;T;T;T

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.95

M_CAP

Benign

0.062

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D

MetaSVM

Benign

-0.31

MutationAssessor

Uncertain

2.7

M;M;M;M;M;M;M

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.7

D;D;D;D;D;D;D

REVEL

Uncertain

0.47

Sift

Uncertain

0.0050

D;D;D;D;D;D;D

Sift4G

Uncertain

0.0060

D;D;D;D;D;D;D

Polyphen

1.0

D;D;D;D;D;D;D

Vest4

0.81

MutPred

0.90

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

0.34

ClinPred

0.98

GERP RS

4.8

Varity_R

0.57

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over