NM_005141.5:c.114G>C

Variant names:

• chr4-154563132-G-C
• rs1339535578
• NM_005141.5:c.114G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005141.5(FGB):​c.114G>C​(p.Glu38Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000081 in 1,235,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
• Consequence: FGB NM_005141.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.12
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.114G>C	p.Glu38Asp	missense splice_region	Exon 1 of 8	NP_005132.2	P02675
	FGB	NM_001382763.1		c.114G>C	p.Glu38Asp	missense splice_region	Exon 1 of 8	NP_001369692.1
	FGB	NM_001382765.1		c.114G>C	p.Glu38Asp	missense splice_region	Exon 1 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.114G>C	p.Glu38Asp	missense splice_region	Exon 1 of 8	ENSP00000306099.4	P02675
	FGB	ENST00000497097.5	TSL:1	n.121G>C		splice_region non_coding_transcript_exon	Exon 1 of 3
	FGB	ENST00000904942.1		c.114G>C	p.Glu38Asp	missense splice_region	Exon 1 of 8	ENSP00000575001.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.10e-7 AC: 1 AN: 1235032 Hom.: 0 Cov.: 18 AF XY: 0.00000162 AC XY: 1 AN XY: 618236

African (AFR) AF: 0.00 AC: 0 AN: 28354

American (AMR) AF: 0.00 AC: 0 AN: 36524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24130

East Asian (EAS) AF: 0.00 AC: 0 AN: 35120

South Asian (SAS) AF: 0.0000133 AC: 1 AN: 75004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49022

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 929842

Other (OTH) AF: 0.00 AC: 0 AN: 52302

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	FGB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Uncertain	23
DANN	Benign	0.69
DEOGEN2	Benign	0.071	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.021
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.94	L
PhyloP100		4.1
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.21
Sift	Benign	0.21	T
Sift4G	Benign	0.22	T
Polyphen		0.0010	B
Vest4		0.13
MutPred		0.50		Loss of glycosylation at S42 (P = 0.1654)
MVP		0.67
MPC		0.15
ClinPred		0.74	D
GERP RS		5.8
PromoterAI		-0.026	Neutral
Varity_R		0.12
gMVP		0.087
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.91		Position offset: 0

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

Other links and lift over

dbSNP: rs1339535578; hg19: chr4-155484284;