dbSNP rs1280924091: FGA:p.Trp843Arg (chr4-154584198-A-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000508.5(FGA):c.2527T>C(p.Trp843Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000667 in 149,930 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 (★).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 32)

Consequence

FGA
NM_000508.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32

Publications

0 publications found

Variant links:

Genes affected

FGA (HGNC:3661): (fibrinogen alpha chain) This gene encodes the alpha subunit of the coagulation factor fibrinogen, which is a component of the blood clot. Following vascular injury, the encoded preproprotein is proteolytically processed by thrombin during the conversion of fibrinogen to fibrin. Mutations in this gene lead to several disorders, including dysfibrinogenemia, hypofibrinogenemia, afibrinogenemia and renal amyloidosis. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that undergoes proteolytic processing. [provided by RefSeq, Jan 2016]

FGA Gene-Disease associations (from GenCC):

familial dysfibrinogenemia
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
congenital afibrinogenemia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
congenital fibrinogen deficiency
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
familial visceral amyloidosis
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
thrombophilia
Inheritance: AR, AD Classification: STRONG Submitted by: Genomics England PanelApp
AFib amyloidosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial hypofibrinogenemia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

FGA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGA	NM_000508.5 link	c.2527T>C	p.Trp843Arg	missense_variant	Exon 6 of 6		NP_000499.1	P02671-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGA	ENST00000651975.2 link	c.2527T>C	p.Trp843Arg	missense_variant	Exon 6 of 6			ENSP00000498441.1		P02671-1

Frequencies

GnomAD3 genomes

AF:

0.00000667

AC:

AN:

149930

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000247

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000667

AC:

AN:

149930

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

73136

show subpopulations

African (AFR)

AF:

0.0000247

AC:

AN:

40550

American (AMR)

AF:

0.00

AC:

AN:

15066

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3450

East Asian (EAS)

AF:

0.00

AC:

AN:

5058

South Asian (SAS)

AF:

0.00

AC:

AN:

4700

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67442

Other (OTH)

AF:

0.00

AC:

AN:

2050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Congenital afibrinogenemia

Uncertain:1

Apr 28, 2021

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.57

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.3

PhyloP100

9.3

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-7.7

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.93

MutPred

0.93

Gain of methylation at W843 (P = 0.0112);

MVP

1.0

MPC

0.49

ClinPred

1.0

GERP RS

5.5

Varity_R

0.96

gMVP

0.96

Mutation Taster

=22/78

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over