Genetic Variant NM_005141.5:c.100A>G (chr4-154563118-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_005141.5(FGB):c.100A>G(p.Asn34Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. N34N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FGB
NM_005141.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.76

Publications

0 publications found

Variant links:

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

FGB links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12131041).

BP6

Variant 4-154563118-A-G is Benign according to our data. Variant chr4-154563118-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2256869.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005141.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FGB	NM_005141.5	MANE Select	c.100A>G	p.Asn34Asp	missense	Exon 1 of 8	NP_005132.2	P02675
FGB	NM_001382763.1		c.100A>G	p.Asn34Asp	missense	Exon 1 of 8	NP_001369692.1
FGB	NM_001382765.1		c.100A>G	p.Asn34Asp	missense	Exon 1 of 8	NP_001369694.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FGB	ENST00000302068.9	TSL:1 MANE Select	c.100A>G	p.Asn34Asp	missense	Exon 1 of 8	ENSP00000306099.4	P02675
FGB	ENST00000497097.5	TSL:1	n.107A>G		non_coding_transcript_exon	Exon 1 of 3
FGB	ENST00000904942.1		c.100A>G	p.Asn34Asp	missense	Exon 1 of 8	ENSP00000575001.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1359364

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

674964

African (AFR)

AF:

0.00

AC:

AN:

31046

American (AMR)

AF:

0.00

AC:

AN:

38490

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25026

East Asian (EAS)

AF:

0.00

AC:

AN:

36714

South Asian (SAS)

AF:

0.00

AC:

AN:

78774

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50204

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5192

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1037502

Other (OTH)

AF:

0.00

AC:

AN:

56416

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.093

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.061

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.0074

LIST_S2

Benign

0.30

M_CAP

Benign

0.018

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-2.2

PhyloP100

1.8

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.48

REVEL

Benign

0.16

Sift

Benign

0.54

Sift4G

Benign

0.66

Polyphen

0.0

Vest4

0.050

MutPred

0.60

Loss of ubiquitination at K29 (P = 0.0768)

MVP

0.50

MPC

0.19

ClinPred

0.067

GERP RS

4.7

PromoterAI

0.030

Neutral

(source)

Varity_R

0.034

gMVP

0.063

Mutation Taster

=91/9

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over