rs6054

Variant names:

• chr4-154568456-C-A
• rs6054
• NM_005141.5:c.794C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-154568456-C-A
• chr4-154568456-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_005141.5(FGB):​c.794C>A​(p.Pro265Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,445,296 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P265L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FGB NM_005141.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.90
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a domain Fibrinogen C-terminal (size 256) in uniprot entity FIBB_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_005141.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGB	NM_005141.5	c.794C>A	p.Pro265Gln	missense_variant	Exon 5 of 8	ENST00000302068.9	NP_005132.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGB	ENST00000302068.9	c.794C>A	p.Pro265Gln	missense_variant	Exon 5 of 8	1	NM_005141.5	ENSP00000306099.4
FGB	ENST00000509493.1	c.137C>A	p.Pro46Gln	missense_variant	Exon 3 of 6	5		ENSP00000426757.1
FGB	ENST00000502545.5	n.775C>A		non_coding_transcript_exon_variant	Exon 5 of 7	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1445296 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 720110

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33190

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.00 AC: 0 AN: 85904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1096894

Other (OTH) AF: 0.00 AC: 0 AN: 59888

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	23
DANN	Benign	0.89
DEOGEN2	Benign	0.22	T;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.6	M;.
PhyloP100		5.9
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.0	D;N
REVEL	Uncertain	0.47
Sift	Benign	0.46	T;T
Sift4G	Uncertain	0.010	D;T
Polyphen		1.0	D;.
Vest4		0.71
MutPred		0.68		Loss of catalytic residue at K264 (P = 0.0954);.;
MVP		0.96
MPC		0.66
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.52
gMVP		0.85
Mutation Taster		=15/85	disease causing

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

Other links and lift over

dbSNP: rs6054; hg19: chr4-155489608;