chr4-154589513-C-T

Position:

chr4-154589513-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong

The ENST00000403106.8(FGA):c.104G>A(p.Arg35His) variant causes a missense change. The variant allele was found at a frequency of 0.0000235 in 1,613,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as 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 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

FGA
ENST00000403106.8 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 5.19

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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, 3 uncertain in ENST00000403106.8

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-154589514-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP5

Variant 4-154589513-C-T is Pathogenic according to our data. Variant chr4-154589513-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-154589513-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGA	NM_021871.4 linkuse as main transcript	c.104G>A	p.Arg35His	missense_variant	2/5	ENST00000403106.8	NP_068657.1
FGA	NM_000508.5 linkuse as main transcript	c.104G>A	p.Arg35His	missense_variant	2/6		NP_000499.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGA	ENST00000403106.8 linkuse as main transcript	c.104G>A	p.Arg35His	missense_variant	2/5	1	NM_021871.4	ENSP00000385981		P02671-2
FGA	ENST00000651975.2 linkuse as main transcript	c.104G>A	p.Arg35His	missense_variant	2/6			ENSP00000498441	P1	P02671-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251286

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1461692

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727160

show subpopulations

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.00000756

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial dysfibrinogenemia

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Aug 29, 2022	The FGA c.104G>A variant is classified as Pathogenic (PS1, PS4, PM1, PM2) The FGA c.104G>A variant is a single nucleotide change in exon 2/6 of the FGA gene, which is predicted to change the amino acid arginine at position 35 in the protein to histidine. The variant has been reported in probands with a clinical presentation of MIM: 616004 (PS4). The variant is rare in population databases (gnomAD allele frequency = 0.0013%; 2 het and 0 hom in 152172 sequenced alleles; highest frequency = 0.0024%, African/African American population) (PM2). Detected in 7x patients with disease in PMID 31064749. This variant is located in a conserved region (PM1). (PMID:34275736) This variant results in the same amino acid change as a previously established variant (PS1). The variant has been reported in dbSNP (rs121909607) and has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 16404). It has not been reported in HGMD. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 08, 2022	Variant summary: FGA c.104G>A (p.Arg35His) 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 1.2e-05 in 251286 control chromosomes (gnomAD). c.104G>A has been reported in the literature in multiple individuals affected with Congenital Dysfibrinogenemia (e.g. Simurda_2020, Szanto_2021, Zhou_2021), including at least one homozygote (Alving_1987). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jul 11, 2022	This FGA missense variant has been identified in the heterozygous state in multiple individuals with congenital dysfibrinogenemia, and is also reported in individuals with FGA-related congenital fibrinogen defects due to biallelic variants. This variant (rs121909607) is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 4/282670 total alleles; 0.0014%; no homozygotes). It has been reported in ClinVar7 (Variation ID 16404). Three bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is evolutionarily conserved across all species assessed. Functional studies support that this missense change impacts protein function. We consider c.104G>A in FGA to be pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 2024	Published functional studies suggest a damaging effect: impaired thrombin polymerization, reduced fibrinogen clottability, reduced fibrinolysis velocity, and delayed release of fibrinopeptide A (PMID: 6830702, 22967385, 22880226); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as R16H using alternate nomenclature; This variant is associated with the following publications: (PMID: 32877852, 33822462, 33443927, 34275736, 32939696, 23962069, 22880226, 22967385, 6830702, 27684817, 6191801, 2738154, 9391726, 25320241, 26577257, 29070135, 29869737, 30856382, 31314131, 30332696, 32166693, 30349899, 2379562, 35949040, 35975558, 31064749, 3618591, 34455742, 7298640, 22169505) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 10, 2024	PM1, PM2_moderate, PM5, PS3, PS4_moderate -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 20, 2022

- -

FGA-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 28, 2024

The FGA c.104G>A variant is predicted to result in the amino acid substitution p.Arg35His. This variant, also referred to as p.Arg16His using legacy nomenclature, has been reported in many patients to be causative for autosomal dominant congenital dysfibrinogenemia (Casini et al. 2015. PubMed ID: 25320241; Siebenlist et al. 1988. PubMed ID: 3345340; Smith et al. 2018. PubMed ID: 30349899; Shapiro et al. 2013. PubMed ID: 23061815). Other missense variants affecting this amino acid (p.Arg35Cys, p.Arg35Ser, p.Arg35Pro) have also been reported in patients with dysfibrinogenemia, suggesting p.Arg35 is important for proper FGA protein function (Miesbach et al. 2010. PubMed ID: 19923982; Shapiro et al. 2013. PubMed ID: 23061815). This variant is reported in 0.0031% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Abnormal bleeding

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Hypofibrinogenemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Dysfibrinogenemia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1989

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

D;.;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.68

D;D;D

MetaSVM

Uncertain

0.26

MutationAssessor

Uncertain

2.7

M;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.3

D;D;.

REVEL

Uncertain

0.36

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.58

MVP

0.87

MPC

0.21

ClinPred

0.97

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.54

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