rs78506343

Positions:

• chr4-154585711-C-A
• chr4-154585711-C-G
• chr4-154585711-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_021871.4(FGA):​c.1718G>T​(p.Arg573Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FGA NM_021871.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 1.02

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-154585711-C-A is Pathogenic according to our data. 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: {Uncertain_significance=1, Likely_pathogenic=1}.
• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.412308). . 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.1718G>T	p.Arg573Leu	missense_variant	5/5	ENST00000403106.8	NP_068657.1
FGA	NM_000508.5	c.1718G>T	p.Arg573Leu	missense_variant	5/6		NP_000499.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGA	ENST00000403106.8	c.1718G>T	p.Arg573Leu	missense_variant	5/5	1	NM_021871.4	ENSP00000385981.3
FGA	ENST00000651975.2	c.1718G>T	p.Arg573Leu	missense_variant	5/6			ENSP00000498441.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461866 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

FGA-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2023

The FGA c.1718G>T variant is predicted to result in the amino acid substitution p.Arg573Leu. This variant is also described using legacy nomenclature as p.Arg554Leu, has been reported in the heterozygous state in multiple individuals with renal amyloidosis (Benson et al. 1993. PubMed ID: 8097946; Hamidi et al. 1998. PubMed ID: 10036586; Haidinger et al. 2013. PubMed ID: 23551149; Meyer et al. 2020. PubMed ID: 32660897). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Familial visceral amyloidosis, Ostertag type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1993

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 26, 2019

Also denoted as R554 due to alternative nomenclature; Identified as heterozygous in multiple individuals with fibrinogen amyloidosis (Benson et al., 1993; Gillmore et al., 2009; Stangou et al., 2010; Haidinger et al., 2013); Published functional studies suggest a damaging effect as the protein fragment harboring the variant converts to globular, beta-sheet rich aggregates that shows amyloid-like properties (Sivalingam and Patel, 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9818055, 27126074, 8097946, 23551149, 19633201, 19073821, 10036586) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	15
DANN	Benign	0.94
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.39	N
M_CAP	Benign	0.021	T
ClinPred		0.065	T
GERP RS		2.1

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

Other links and lift over

dbSNP: rs78506343; hg19: chr4-155506863; COSMIC: COSV57399852;