rs2070025

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_021871.4(FGA):c.16A>G(p.Ile6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,557,848 control chromosomes in the GnomAD database, including 193 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0035 ( 17 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 176 hom. )

Consequence

FGA
NM_021871.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0180

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0013471544).

BP6

Variant 4-154590672-T-C is Benign according to our data. Variant chr4-154590672-T-C is described in ClinVar as [Benign]. Clinvar id is 347823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0796 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGA	NM_021871.4 linkuse as main transcript	c.16A>G	p.Ile6Val	missense_variant	1/5	ENST00000403106.8
FGA	NM_000508.5 linkuse as main transcript	c.16A>G	p.Ile6Val	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGA	ENST00000403106.8 linkuse as main transcript	c.16A>G	p.Ile6Val	missense_variant	1/5	1	NM_021871.4		P02671-2
FGA	ENST00000651975.2 linkuse as main transcript	c.16A>G	p.Ile6Val	missense_variant	1/6			P1	P02671-1

Frequencies

GnomAD3 genomes

AF:

0.00349

AC:

531

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.0856

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00525

GnomAD3 exomes

AF:

0.00764

AC:

1264

AN:

165434

Hom.:

AF XY:

0.00708

AC XY:

616

AN XY:

87022

show subpopulations

Gnomad AFR exome

AF:

0.00112

Gnomad AMR exome

AF:

0.000238

Gnomad ASJ exome

AF:

0.000694

Gnomad EAS exome

AF:

0.0969

Gnomad SAS exome

AF:

0.000992

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000759

Gnomad OTH exome

AF:

0.00545

GnomAD4 exome

AF:

0.00273

AC:

3837

AN:

1405516

Hom.:

176

Cov.:

AF XY:

0.00256

AC XY:

1775

AN XY:

693736

show subpopulations

Gnomad4 AFR exome

AF:

0.000436

Gnomad4 AMR exome

AF:

0.000193

Gnomad4 ASJ exome

AF:

0.000277

Gnomad4 EAS exome

AF:

0.0876

Gnomad4 SAS exome

AF:

0.000992

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000379

Gnomad4 OTH exome

AF:

0.00830

GnomAD4 genome

AF:

0.00351

AC:

534

AN:

152332

Hom.:

Cov.:

AF XY:

0.00400

AC XY:

298

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00106

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.0862

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00308

Hom.:

Bravo

AF:

0.00384

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00481

AC:

537

Asia WGS

AF:

0.0470

AC:

164

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	This variant is associated with the following publications: (PMID: 32877852) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Congenital afibrinogenemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.65

Cadd

Benign

6.0

Dann

Benign

0.83

DEOGEN2

Benign

0.21

T;.;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.49

T;T;T

MetaRNN

Benign

0.0013

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.34

N;N;.

REVEL

Benign

0.036

Sift

Benign

0.52

T;T;.

Sift4G

Benign

0.60

T;T;T

Polyphen

0.051

B;B;.

Vest4

0.028

MVP

0.17

MPC

0.055

ClinPred

0.0016

GERP RS

0.59

Varity_R

0.019

gMVP

0.12

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over