rs121909606

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The NM_021871.4(FGA):c.103C>T(p.Arg35Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,694 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R35N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

FGA
NM_021871.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 6.58

Publications

30 publications found

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 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

FGA links:

ENSG00000306549 (HGNC:):

ENSG00000306549 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_021871.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-154589513-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 16404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.746

PP5

Variant 4-154589514-G-A is Pathogenic according to our data. Variant chr4-154589514-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGA	NM_021871.4 link	c.103C>T	p.Arg35Cys	missense_variant	Exon 2 of 5	ENST00000403106.8	NP_068657.1
FGA	NM_000508.5 link	c.103C>T	p.Arg35Cys	missense_variant	Exon 2 of 6		NP_000499.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
FGA	ENST00000403106.8 link	c.103C>T	p.Arg35Cys	missense_variant	Exon 2 of 5	1	NM_021871.4	ENSP00000385981.3
FGA	ENST00000651975.2 link	c.103C>T	p.Arg35Cys	missense_variant	Exon 2 of 6			ENSP00000498441.1
ENSG00000306549	ENST00000819308.1 link	n.137+2750G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251232

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000205

AC:

AN:

1461578

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727120

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53222

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111918

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial dysfibrinogenemia

Pathogenic:2

Aug 07, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: FGA c.103C>T (p.Arg35Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251232 control chromosomes. In a cross-sectional review of the literature, c.103C>T has been reported as the "A alpha Arg16Cys" variant in heterozygous or homozygous genotypes in multple individuals affected with features of Dysfibrinogenemia, some of whom reported multiple coagulation factor deficiencies (example, Galanakis_1993, Miesbach_2010, Preisler_2021). The inheritance of dysfibrinogemia is most often autosomal dominant with reports of severely affected homozygotes as well some variably affected heterozygotes and some reportedly asymptomatic heterozygotes. The range of phenotypes encountered can vary from undue bleeding, easy bruising to those experienced thrombotic events (Miesbach_2010). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrating an impact on protein function was not ascertained in the context of this evaluation. The following publications have been ascertained in the context of this evaluation (PMID: 8457654, 15009465, 19923982, 33477601). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jun 09, 2023

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 16846481). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with FGA related disorder (ClinVar ID: VCV000016399 /PMID: 8457654). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 22967385, 26676819, 30349899). Different missense changes at the same codon (p.Arg35Gly, p.Arg35His, p.Arg35Pro, p.Arg35Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016404, VCV000627196, VCV000627199, VCV001684488 /PMID: 19923982, 23061815, 7298640). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

FGA-related disorder

Pathogenic:1

Jan 04, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The FGA c.103C>T variant is predicted to result in the amino acid substitution p.Arg35Cys. This variant is also described using legacy nomenclature as p.Arg16Cys, has been reported to be causative for autosomal dominant dysfibrinogenemia in several families (Miesbach et al. 2010. PubMed ID: 19923982; Galanakis et al. 1993. PubMed ID: 8457654; Jiang et al. 2012. PubMed ID: 22967385). Other missense variants affecting amino acid residue p.Arg35 have also been reported in many patients with dysfibrinogenemia suggesting p.Arg35 is important for proper FGA protein function (see p.Arg35Ser Miesbach et al. 2010. PubMed ID: 19923982; p.Arg35His Soya et al. 2012. PubMed ID: 22880226; p.Ser35Pro Shapiro et al. 2013. PubMed ID: 23061815). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Jul 26, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM1, PM2_moderate, PM5, PS3, PS4_moderate -

Dysfibrinogenemia

Pathogenic:1

Jul 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

D;.;.

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.75

D;D;D

MetaSVM

Uncertain

0.26

MutationAssessor

Uncertain

2.7

M;M;.

PhyloP100

6.6

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.1

D;D;.

REVEL

Uncertain

0.44

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.82

MutPred

0.21

Loss of disorder (P = 0.0089);Loss of disorder (P = 0.0089);Loss of disorder (P = 0.0089);

MVP

0.84

MPC

0.29

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.85

gMVP

0.58

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over