4-154569794-C-G

Variant names:

• chr4-154569794-C-G
• NM_005141.5:c.1239C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005141.5(FGB):​c.1239C>G​(p.Asp413Glu) 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 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FGB NM_005141.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.237

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGB	NM_005141.5	c.1239C>G	p.Asp413Glu	missense_variant	Exon 7 of 8	ENST00000302068.9	NP_005132.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGB	ENST00000302068.9	c.1239C>G	p.Asp413Glu	missense_variant	Exon 7 of 8	1	NM_005141.5	ENSP00000306099.4
FGB	ENST00000509493.1	c.582C>G	p.Asp194Glu	missense_variant	Exon 5 of 6	5		ENSP00000426757.1
FGB	ENST00000502545.5	n.939+487C>G		intron_variant	Intron 6 of 6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461834 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	4.4
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	T;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.0	M;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;.
Vest4		0.92
MutPred		0.96		Gain of catalytic residue at W415 (P = 0.0336);.;
MVP		0.67
MPC		0.67
ClinPred		0.99	D
GERP RS		-11
Varity_R		0.93
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-155490946;