rs755117226

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_021871.4(FGA):c.502C>T(p.Arg168Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000149 in 1,613,652 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

FGA
NM_021871.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 3.77

Variant links:

Genes affected

FGA (HGNC:3661): (fibrinogen alpha chain) This gene encodes the alpha subunit of the coagulation factor fibrinogen, which is a component of the blood clot. Following vascular injury, the encoded preproprotein is proteolytically processed by thrombin during the conversion of fibrinogen to fibrin. Mutations in this gene lead to several disorders, including dysfibrinogenemia, hypofibrinogenemia, afibrinogenemia and renal amyloidosis. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that undergoes proteolytic processing. [provided by RefSeq, Jan 2016]

FGA links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 16 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-154587520-G-A is Pathogenic according to our data. Variant chr4-154587520-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 402230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGA	NM_021871.4 linkuse as main transcript	c.502C>T	p.Arg168Ter	stop_gained	4/5	ENST00000403106.8
FGA	NM_000508.5 linkuse as main transcript	c.502C>T	p.Arg168Ter	stop_gained	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGA	ENST00000403106.8 linkuse as main transcript	c.502C>T	p.Arg168Ter	stop_gained	4/5	1	NM_021871.4		P02671-2
FGA	ENST00000651975.2 linkuse as main transcript	c.502C>T	p.Arg168Ter	stop_gained	4/6			P1	P02671-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151954

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251358

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461698

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

151954

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74204

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000557

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial visceral amyloidosis, Ostertag type;C0272350:Familial dysfibrinogenemia;C2584774:Congenital afibrinogenemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 02, 2021

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 06, 2017

For these reasons, this variant has been classified as Pathogenic. Analysis of patient-derived plasma was unable to detect fibrinogen via clotting and immunological methods in an individual carrying this variant along with another rare FGA variant (PMID: 26763372). This variant has been reported in the homozygous or compound heterozygous state in individuals affected with afibrinogenaemia (PMID: 10887149, 26763372). ClinVar contains an entry for this variant (Variation ID: 402230). This variant is present in population databases (rs755117226, ExAC 0.001%). This sequence change results in a premature translational stop signal in the FGA gene (p.Arg168*). This is expected to delete the last 477 amino acids (~74%) of the FGA protein. -

Congenital afibrinogenemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Sep 26, 2015

The c.502C>T, p.Arg168ter variant has been seen in the homozygous state in four individuals: one Norwegian (Fellowes et al., 2000) and three Sardinian (Asselta et al., 2001), who were diagnosed with congenital afibrinogenemia. All these individuals had immunologically very low; to undetectable fibrinogen levels suggesting that loss-of-function is a mechanism of disease. Furthermore, this variant was shown to co-segregate with disease and family members who were heterozygous for this variant were unaffected (Fellowes et al., 2000). Arginine at position 168 is evolutionarily conserved and it is present within the coil-coil domain of the protein. This domain is critical for protein assembly. Indeed, an in vitro study using the p.Arg168ter variant showed an absence of secreted fibrinogen because of its inability to assemble with the other fibrinogen subunits (Î² and Î³) (Asselta et al., 2001). This variant is either absent or present at a very low frequency, with no homozygotes, in the population databases (1000 Genome, Exome Sequencing Project and ExAC). In summary, this variant meets our criteria for a Pathogenic classification. We have confirmed this finding in our laboratory using Sanger sequencing. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.50

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.90

MutationTaster

Benign

1.0

A;D

Vest4

0.85

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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