4-154586438-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_021871.4(FGA):c.991A>G(p.Thr331Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 1,613,298 control chromosomes in the GnomAD database, including 60,604 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.29 ( 6817 hom., cov: 31)

Exomes 𝑓: 0.27 ( 53787 hom. )

Consequence

FGA
NM_021871.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6O:1

Conservation

PhyloP100: -7.95

Publications

123 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:

ENSG00000306549 (HGNC:):

ENSG00000306549 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.001392E-4).

BP6

Variant 4-154586438-T-C is Benign according to our data. Variant chr4-154586438-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 16420.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGA	NM_021871.4 link	c.991A>G	p.Thr331Ala	missense_variant	Exon 5 of 5	ENST00000403106.8	NP_068657.1	P02671-2
FGA	NM_000508.5 link	c.991A>G	p.Thr331Ala	missense_variant	Exon 5 of 6		NP_000499.1	P02671-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FGA	ENST00000403106.8 link	c.991A>G	p.Thr331Ala	missense_variant	Exon 5 of 5	1	NM_021871.4	ENSP00000385981.3	P02671-2
FGA	ENST00000651975.2 link	c.991A>G	p.Thr331Ala	missense_variant	Exon 5 of 6			ENSP00000498441.1	P02671-1
ENSG00000306549	ENST00000819308.1 link	n.-190T>C		upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.294

AC:

44526

AN:

151580

Hom.:

6806

Cov.:

show subpopulations

Gnomad AFR

AF:

0.363

Gnomad AMI

AF:

0.257

Gnomad AMR

AF:

0.248

Gnomad ASJ

AF:

0.182

Gnomad EAS

AF:

0.445

Gnomad SAS

AF:

0.303

Gnomad FIN

AF:

0.312

Gnomad MID

AF:

0.212

Gnomad NFE

AF:

0.254

Gnomad OTH

AF:

0.260

GnomAD2 exomes

AF:

0.286

AC:

71751

AN:

251264

AF XY:

0.285

show subpopulations

Gnomad AFR exome

AF:

0.369

Gnomad AMR exome

AF:

0.244

Gnomad ASJ exome

AF:

0.186

Gnomad EAS exome

AF:

0.455

Gnomad FIN exome

AF:

0.318

Gnomad NFE exome

AF:

0.254

Gnomad OTH exome

AF:

0.251

GnomAD4 exome

AF:

0.266

AC:

388747

AN:

1461600

Hom.:

53787

Cov.:

AF XY:

0.267

AC XY:

194139

AN XY:

727100

show subpopulations

African (AFR)

AF:

0.363

AC:

12149

AN:

33480

American (AMR)

AF:

0.242

AC:

10808

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.186

AC:

4858

AN:

26136

East Asian (EAS)

AF:

0.467

AC:

18556

AN:

39700

South Asian (SAS)

AF:

0.327

AC:

28163

AN:

86250

European-Finnish (FIN)

AF:

0.315

AC:

16841

AN:

53418

Middle Eastern (MID)

AF:

0.218

AC:

1258

AN:

5764

European-Non Finnish (NFE)

AF:

0.253

AC:

280735

AN:

1111748

Other (OTH)

AF:

0.255

AC:

15379

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

18706

37412

56117

74823

93529

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9676

19352

29028

38704

48380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.294

AC:

44567

AN:

151698

Hom.:

6817

Cov.:

AF XY:

0.295

AC XY:

21846

AN XY:

74128

show subpopulations

African (AFR)

AF:

0.363

AC:

15035

AN:

41370

American (AMR)

AF:

0.248

AC:

3773

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.182

AC:

630

AN:

3466

East Asian (EAS)

AF:

0.445

AC:

2280

AN:

5122

South Asian (SAS)

AF:

0.304

AC:

1459

AN:

4796

European-Finnish (FIN)

AF:

0.312

AC:

3290

AN:

10532

Middle Eastern (MID)

AF:

0.204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.254

AC:

17264

AN:

67878

Other (OTH)

AF:

0.258

AC:

543

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1620

3239

4859

6478

8098

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

468

936

1404

1872

2340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.264

Hom.:

9573

Bravo

AF:

0.293

TwinsUK

AF:

0.252

AC:

934

ALSPAC

AF:

0.257

AC:

989

ESP6500AA

AF:

0.364

AC:

1603

ESP6500EA

AF:

0.252

AC:

2168

ExAC

AF:

0.287

AC:

34860

Asia WGS

AF:

0.326

AC:

1129

AN:

3478

EpiCase

AF:

0.242

EpiControl

AF:

0.247

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:1

Apr 23, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 32853977, 26139837, 18057060, 24821635, 10318664, 17433418, 19652888, 23894515, 19143925, 22353194, 10910940) -

Congenital afibrinogenemia

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Familial visceral amyloidosis, Ostertag type

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Venous thromboembolism, susceptibility to

Other:1

Mar 01, 2006

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.0030

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.20

T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0070

LIST_S2

Benign

0.48

T;T

MetaRNN

Benign

0.00030

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.12

N;N

PhyloP100

-8.0

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.092

Sift

Benign

0.47

T;T

Sift4G

Benign

0.83

T;T

Polyphen

0.025

B;B

Vest4

0.017

MPC

0.058

ClinPred

0.0091

GERP RS

-6.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.021

gMVP

0.18

Mutation Taster

=98/2

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over