rs121909623

Positions:

• chr4-154567688-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1_Moderate PM2 PP3_Strong

The NM_005141.5(FGB):​c.586C>T​(p.Arg196Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,254 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 Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FGB NM_005141.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1 O:1
• Conservation: PhyloP100: 1.81

Genes affected

FGB (HGNC:3662): (fibrinogen beta chain) The protein encoded by this gene is the beta 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. Fibrinogen serves key roles in hemostasis and antimicrobial host defense. Mutations in this gene lead to several disorders, including afibrinogenemia, dysfibrinogenemia, hypodysfibrinogenemia and thrombotic tendency. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PS1: Transcript NM_005141.5 (FGB) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGB	NM_005141.5	c.586C>T	p.Arg196Cys	missense_variant	4/8	ENST00000302068.9	NP_005132.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGB	ENST00000302068.9	c.586C>T	p.Arg196Cys	missense_variant	4/8	1	NM_005141.5	ENSP00000306099	P1
FGB	ENST00000509493.1	c.-72C>T		5_prime_UTR_variant	2/6	5		ENSP00000426757
FGB	ENST00000473984.1	n.499C>T		non_coding_transcript_exon_variant	3/3	2
FGB	ENST00000502545.5	n.567C>T		non_coding_transcript_exon_variant	4/7	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251178 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135746

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461254 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726994

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

FGB-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 14, 2024

The FGB c.586C>T variant is predicted to result in the amino acid substitution p.Arg196Cys. This variant has been reported in multiple individuals with congenital dysfibrinogenemia (Lounes et al. 2001. PubMed ID: 11468164; Chinni et al. 2018. PubMed ID: 30418131; Table S3, Downes et al. 2019. PubMed ID: 31064749; Table S3, Gindele et al. 2021. PubMed ID: 33807613; Simurda et al. 2024. PubMed ID: 38251440). In vitro studies suggest that this variant disrupts fibrinogen polymerization, leading to impaired clot formation (Lounes et al. 2001. PubMed ID: 11468164). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is interpreted as likely pathogenic. -

Hypofibrinogenemia Uncertain:1

Uncertain significance, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

FIBRINOGEN LONGMONT Other:1

other, no assertion criteria provided

literature only

OMIM

Mar 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.90		Loss of MoRF binding (P = 0.0026);
MVP		0.95
MPC		0.79
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.60
gMVP		0.66

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

Other links and lift over

dbSNP: rs121909623; hg19: chr4-155488840; COSMIC: COSV57417626; COSMIC: COSV57417626;