4-154589513-C-T

Variant names:

• chr4-154589513-C-T
• rs121909607
• NM_021871.4:c.104G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM5 PP5_Very_Strong

The NM_021871.4(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 NM_021871.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 5.19
• Publications: 25 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

ENSG00000306549 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 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
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP5: Variant 4-154589513-C-T is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGA	NM_021871.4	c.104G>A	p.Arg35His	missense_variant	Exon 2 of 5	ENST00000403106.8	NP_068657.1
FGA	NM_000508.5	c.104G>A	p.Arg35His	missense_variant	Exon 2 of 6		NP_000499.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGA	ENST00000403106.8	c.104G>A	p.Arg35His	missense_variant	Exon 2 of 5	1	NM_021871.4	ENSP00000385981.3
FGA	ENST00000651975.2	c.104G>A	p.Arg35His	missense_variant	Exon 2 of 6			ENSP00000498441.1
ENSG00000306549	ENST00000819308.1	n.137+2749C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152172 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251286 AF XY: 0.0000147

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461692 Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19 AN XY: 727160

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53284

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111956

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74338

African (AFR) AF: 0.0000241 AC: 1 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000238 Hom.: 0

Bravo AF: 0.00000756

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial dysfibrinogenemia Pathogenic:3

Apr 08, 2022

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.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. -

Aug 29, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 11, 2022

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 17, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 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) -

Jul 10, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1, PM2_moderate, PM5, PS3, PS4_moderate -

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

Jan 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FGA-related disorder Pathogenic:1

May 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Hypofibrinogenemia Pathogenic:1

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Dysfibrinogenemia Pathogenic:1

Jul 01, 1989

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	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.68	D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.7	M;M;.
PhyloP100		5.2
PrimateAI	Uncertain	0.52	T
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	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.54
Mutation Taster		=18/82	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: rs121909607; hg19: chr4-155510665; COSMIC: COSV57397021;