rs78506343

Variant names:

• chr4-154585711-C-A
• rs78506343
• NM_021871.4:c.1718G>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM2 PM5 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. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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)
  • 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
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• familial dysfibrinogenemia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• congenital afibrinogenemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• congenital fibrinogen deficiency

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• familial visceral amyloidosis

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• thrombophilia

  Inheritance: AR, AD Classification: STRONG Submitted by: Genomics England PanelApp
• AFib amyloidosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial hypofibrinogenemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-154585712-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 16411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 VariationId is 16408.
• BP4: Computational evidence support a benign effect (REVEL=0.253). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGA	NM_021871.4	c.1718G>T	p.Arg573Leu	missense_variant	Exon 5 of 5	ENST00000403106.8	NP_068657.1
FGA	NM_000508.5	c.1718G>T	p.Arg573Leu	missense_variant	Exon 5 of 6		NP_000499.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGA	ENST00000403106.8	c.1718G>T	p.Arg573Leu	missense_variant	Exon 5 of 5	1	NM_021871.4	ENSP00000385981.3
FGA	ENST00000651975.2	c.1718G>T	p.Arg573Leu	missense_variant	Exon 5 of 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

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

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

Feb 07, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Uncertain:1

Jul 26, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		1.0
ClinPred		0.065	T
GERP RS		2.1
Varity_R		0.15
Mutation Taster		=12/88	disease causing (ClinVar)

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

Other links and lift over

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