rs121913087

Variant names:

• chr4-154606933-G-A
• rs121913087
• NM_021870.3:c.901C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-154606933-G-A
• chr4-154606933-G-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_021870.3(FGG):​c.901C>T​(p.Arg301Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,054 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. R301H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: FGG NM_021870.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 4.55
• Publications: 14 publications found

Genes affected

FGG (HGNC:3694): (fibrinogen gamma chain) The protein encoded by this gene is the gamma component of fibrinogen, a blood-borne glycoprotein comprised of three pairs of nonidentical polypeptide chains. Following vascular injury, fibrinogen is cleaved by thrombin to form fibrin which is the most abundant component of blood clots. In addition, various cleavage products of fibrinogen and fibrin regulate cell adhesion and spreading, display vasoconstrictor and chemotactic activities, and are mitogens for several cell types. Mutations in this gene lead to several disorders, including dysfibrinogenemia, hypofibrinogenemia and thrombophilia. Alternative splicing results in transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

FGG Gene-Disease associations (from GenCC):

• congenital fibrinogen deficiency

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• familial dysfibrinogenemia

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

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
• congenital afibrinogenemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• familial hypofibrinogenemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-154606932-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 4-154606933-G-A is Pathogenic according to our data. Variant chr4-154606933-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16361.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
FGG	NM_021870.3	c.901C>T	p.Arg301Cys	missense_variant	Exon 8 of 9	ENST00000336098.8	NP_068656.2
FGG	NM_000509.6	c.901C>T	p.Arg301Cys	missense_variant	Exon 8 of 10		NP_000500.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGG	ENST00000336098.8	c.901C>T	p.Arg301Cys	missense_variant	Exon 8 of 9	2	NM_021870.3	ENSP00000336829.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461054 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726784

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111508

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial dysfibrinogenemia Pathogenic:4

-

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 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: FGG c.901C>T (p.Arg301Cys) 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 was absent in 250032 control chromosomes. c.901C>T has been reported in the literature in multiple individuals affected with congenital dysfibrinogenemia and/or comprehensively sequenced cohorts of patients with bleeding, thrombotic, and platelet disorders (example, PMID: 7654933, 31064749, 10911375, 29351094). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been ascertained in the context of this evaluation. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 13, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP3_Moderate+PM5+PS4+PP1+PP4 -

not provided Pathogenic:3

Feb 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 301 of the FGG protein (p.Arg301Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dysfibrinoginemia (PMID: 2971042, 7654933, 20386430, 29351094, 31295712, 31314131, 32877852, 35048620). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg275Cys. ClinVar contains an entry for this variant (Variation ID: 16361). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FGG protein function with a positive predictive value of 80%. Studies have shown that this missense change alters FGG gene expression (PMID: 2971042). This variant disrupts the p.Arg301 amino acid residue in FGG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20508898, 20546853, 30349899, 30512152, 35063457). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Apr 26, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 14, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PP5, PM1, PM2_moderate, PM5, PS3, PS4_moderate -

Hypofibrinogenemia Pathogenic:1

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

FGG-related disorder Pathogenic:1

Sep 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FGG c.901C>T variant is predicted to result in the amino acid substitution p.Arg301Cys. This variant is also described using legacy nomenclature as p.Arg275Cys, has been reported in the heterozygous state in several patients with dysfibrinogenemia (Borrell et al. 1995. PubMed ID: 7654933; Rein et al. 2010. PubMed ID: 20386430; Wang et al. 2018. PubMed ID: 29351094). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Afibrinogenemia Pathogenic:1

-

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

FIBRINOGEN TOKYO 2 Other:1

Sep 26, 2014

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	.;.;D;T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.5	H;.;H;.
PhyloP100		4.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.7	D;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.94
MutPred		0.85		.;Gain of catalytic residue at L310 (P = 0.0184);.;Gain of catalytic residue at L310 (P = 0.0184);
MVP		0.93
MPC		0.94
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.91
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121913087; hg19: chr4-155528085; COSMIC: COSV60195240; COSMIC: COSV60195240;