NM_021870.3:c.418T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_021870.3(FGG):c.418T>C(p.Tyr140His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00335 in 1,584,110 control chromosomes in the GnomAD database, including 137 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 79 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 58 hom. )

Consequence

FGG
NM_021870.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.81

Publications

12 publications found

Variant links:

Genes affected

FGG (HGNC:3694): (fibrinogen gamma chain) The protein encoded by this gene is the gamma 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. Mutations in this gene lead to several disorders, including dysfibrinogenemia, hypofibrinogenemia and thrombophilia. Alternative splicing results in transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

FGG Gene-Disease associations (from GenCC):

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

FGG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024793744).

BP6

Variant 4-154610181-A-G is Benign according to our data. Variant chr4-154610181-A-G is described in ClinVar as Benign. ClinVar VariationId is 347830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0581 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021870.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGG	NM_021870.3	MANE Select	c.418T>C	p.Tyr140His	missense	Exon 5 of 9	NP_068656.2
	FGG	NM_000509.6		c.418T>C	p.Tyr140His	missense	Exon 5 of 10	NP_000500.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FGG	ENST00000336098.8	TSL:2 MANE Select	c.418T>C	p.Tyr140His	missense	Exon 5 of 9	ENSP00000336829.3
FGG	ENST00000404648.7	TSL:1	c.418T>C	p.Tyr140His	missense	Exon 5 of 10	ENSP00000384860.3
FGG	ENST00000407946.5	TSL:5	c.418T>C	p.Tyr140His	missense	Exon 5 of 9	ENSP00000384552.1

Frequencies

GnomAD3 genomes

AF:

0.0173

AC:

2632

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0602

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00576

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.00474

AC:

1189

AN:

250840

AF XY:

0.00341

show subpopulations

Gnomad AFR exome

AF:

0.0630

Gnomad AMR exome

AF:

0.00305

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000291

Gnomad OTH exome

AF:

0.00426

GnomAD4 exome

AF:

0.00187

AC:

2680

AN:

1431846

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

1160

AN XY:

714272

show subpopulations

African (AFR)

AF:

0.0611

AC:

1999

AN:

32730

American (AMR)

AF:

0.00350

AC:

156

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.0000386

AC:

AN:

25920

East Asian (EAS)

AF:

0.00

AC:

AN:

39512

South Asian (SAS)

AF:

0.000105

AC:

AN:

85642

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53344

Middle Eastern (MID)

AF:

0.00332

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.000239

AC:

259

AN:

1084958

Other (OTH)

AF:

0.00399

AC:

237

AN:

59392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

122

243

365

486

608

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

210

280

350

<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:

0.0173

AC:

2631

AN:

152264

Hom.:

Cov.:

AF XY:

0.0165

AC XY:

1228

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0600

AC:

2494

AN:

41546

American (AMR)

AF:

0.00569

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68018

Other (OTH)

AF:

0.0109

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

134

268

401

535

669

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.00708

Hom.:

Bravo

AF:

0.0200

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.0561

AC:

247

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00594

AC:

721

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000533

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Congenital afibrinogenemia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.41

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.2

PhyloP100

2.8

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.5

REVEL

Benign

0.26

Sift

Benign

0.17

Sift4G

Benign

0.41

Polyphen

0.013

Vest4

0.064

MVP

0.76

MPC

0.29

ClinPred

0.023

GERP RS

5.7

Varity_R

0.26

gMVP

0.61

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over