rs121909613

Positions:

• chr4-154585712-G-A
• chr4-154585712-G-C
• chr4-154585712-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM2 PM5 PP5_Very_Strong BP4

The ENST00000403106.8(FGA):​c.1717C>T​(p.Arg573Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R573H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGA ENST00000403106.8 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: -1.01

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-154585711-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 16408.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP5: Variant 4-154585712-G-A is Pathogenic according to our data. Variant chr4-154585712-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.210161). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGA	NM_021871.4	c.1717C>T	p.Arg573Cys	missense_variant	5/5	ENST00000403106.8	NP_068657.1
FGA	NM_000508.5	c.1717C>T	p.Arg573Cys	missense_variant	5/6		NP_000499.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGA	ENST00000403106.8	c.1717C>T	p.Arg573Cys	missense_variant	5/5	1	NM_021871.4	ENSP00000385981
FGA	ENST00000651975.2	c.1717C>T	p.Arg573Cys	missense_variant	5/6			ENSP00000498441	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial visceral amyloidosis, Ostertag type;C0272350:Familial dysfibrinogenemia;C2584774:Congenital afibrinogenemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 28, 2021

- -

Deep venous thrombosis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

-

- -

FIBRINOGEN DUSART Other:1

other, no assertion criteria provided

literature only

OMIM

Nov 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	9.9
DANN	Benign	0.91
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.16	N
M_CAP	Benign	0.062	D
MutationTaster	Benign	1.0	N;N
ClinPred		0.74	D
GERP RS		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs121909613; hg19: chr4-155506864;