NM_005141.5:c.605T>A

Variant names:

• chr4-154567707-T-A
• rs121909624
• NM_005141.5:c.605T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_005141.5(FGB):​c.605T>A​(p.Leu202Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGB NM_005141.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.64
• Publications: 4 publications found

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]

FGB Gene-Disease associations (from GenCC):

• congenital fibrinogen deficiency

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• thrombophilia

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial hypofibrinogenemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 4-154567707-T-A is Pathogenic according to our data. Variant chr4-154567707-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 16395.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005141.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGB	NM_005141.5	MANE Select	c.605T>A	p.Leu202Gln	missense	Exon 4 of 8	NP_005132.2	P02675
	FGB	NM_001382763.1		c.605T>A	p.Leu202Gln	missense	Exon 4 of 8	NP_001369692.1
	FGB	NM_001382765.1		c.605T>A	p.Leu202Gln	missense	Exon 4 of 8	NP_001369694.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGB	ENST00000302068.9	TSL:1 MANE Select	c.605T>A	p.Leu202Gln	missense	Exon 4 of 8	ENSP00000306099.4	P02675
	FGB	ENST00000904942.1		c.605T>A	p.Leu202Gln	missense	Exon 4 of 8	ENSP00000575001.1
	FGB	ENST00000904940.1		c.605T>A	p.Leu202Gln	missense	Exon 4 of 8	ENSP00000574999.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital afibrinogenemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
PhyloP100		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.78
Mutation Taster		=213/87	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.65		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.65		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs121909624; hg19: chr4-155488859;