chr4-154611883-G-C

Position:

chr4-154611883-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP5BP4BS1_Supporting

The NM_021870.3(FGG):c.323C>G(p.Ala108Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00303 in 1,611,606 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.0022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 12 hom. )

Consequence

FGG
NM_021870.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:15U:3B:1

Conservation

PhyloP100: 1.97

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PP5

Variant 4-154611883-G-C is Pathogenic according to our data. Variant chr4-154611883-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547969.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=3, Likely_benign=1, Likely_pathogenic=10}. Variant chr4-154611883-G-C is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.011885256). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00217 (331/152266) while in subpopulation NFE AF= 0.00404 (275/68018). AF 95% confidence interval is 0.00365. There are 0 homozygotes in gnomad4. There are 128 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGG	NM_021870.3 link	c.323C>G	p.Ala108Gly	missense_variant	4/9	ENST00000336098.8	NP_068656.2	P02679-1
FGG	NM_000509.6 link	c.323C>G	p.Ala108Gly	missense_variant	4/10		NP_000500.2	P02679-2A0A140VJJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGG	ENST00000336098.8 link	c.323C>G	p.Ala108Gly	missense_variant	4/9	2	NM_021870.3	ENSP00000336829.3		P02679-1

Frequencies

GnomAD3 genomes

AF:

0.00218

AC:

332

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00406

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00195

AC:

486

AN:

249532

Hom.:

AF XY:

0.00210

AC XY:

283

AN XY:

134996

show subpopulations

Gnomad AFR exome

AF:

0.000804

Gnomad AMR exome

AF:

0.000291

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000393

Gnomad FIN exome

AF:

0.00123

Gnomad NFE exome

AF:

0.00355

Gnomad OTH exome

AF:

0.00181

GnomAD4 exome

AF:

0.00312

AC:

4554

AN:

1459340

Hom.:

Cov.:

AF XY:

0.00322

AC XY:

2338

AN XY:

726064

show subpopulations

Gnomad4 AFR exome

AF:

0.000718

Gnomad4 AMR exome

AF:

0.000672

Gnomad4 ASJ exome

AF:

0.00161

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000592

Gnomad4 FIN exome

AF:

0.00106

Gnomad4 NFE exome

AF:

0.00383

Gnomad4 OTH exome

AF:

0.00161

GnomAD4 genome

AF:

0.00217

AC:

331

AN:

152266

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

128

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.000529

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00404

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00321

Hom.:

Bravo

AF:

0.00187

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.000909

AC:

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.00209

AC:

254

EpiCase

AF:

0.00366

EpiControl

AF:

0.00399

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:15Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Congenital afibrinogenemia

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, flagged submission	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 01, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.323C>G (p.Ala108Gly) in FGG gene has been reported in heterozygous state in at least 10 individuals, and in a compound heterozygous state in at least one individual, all of whom are reported to have mild-moderate bleeding disorders with or without thromboembolism. This includes four individuals diagnosed with hypofibrinogenemia and one individual diagnosed with hypodysfibrinogenemia (Wypasek et al.,2019) . This variant has been reported to the ClinVar database as Likely Pathogenic. The p.Ala108Gly variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.1986% is reported in gnomAD. The amino acid Ala at position 108 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Ala108Gly in FGG is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -

not provided

Pathogenic:3Benign:1

Likely benign, flagged submission	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 31, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 06, 2021	PP1, PM2, PM3, PS4_Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	FGG: PP4:Strong, PS4, PP2, PS3:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Familial dysfibrinogenemia

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Heterozygous Missense variant c.323C>G in Exon 4 of the FGG gene that results in the amino acid substitution p.Ala108Gly was identified. The observed variant has a maximum allele frequency of 0.00195/0.00229% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is diseasecausing. ClinVar has also classified this variant as ConflictingInterpretations (Variant ID: 547969). This variant is reported in hemizygous for hypofibrinogenemia (Couzen et al., 2022). For these reasons, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 30, 2023	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 04, 2020	The p.Ala108Gly variant in FGG has been reported in at least 5 individuals with hypofibrinogenemia, 2 individuals with dysfibrinogenemia, 1 individual with thrombocytopenia, and 1 individual with a clotting disorder. It segregated with disease in 3 affected individuals from 1 family, but that family also harbored a variant in FGB that may partially or fully explain the phenotype (Brennan 2000 PMID: 10688828, Bell 2011 PMID: 21228398, Smith 2018 PMID: 30349899, Downes 2019 PMID: 31064749, Guglielmone 2019 PMID: 30632992, Ferrari 2019, Moret 2019 PMID: 31295712, Saes 2019 PMID: 30431218). It has also been identified in 0.36% (462/128216) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Moderate, PP1, BS1, BP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 17, 2024	Variant summary: FGG c.323C>G (p.Ala108Gly) results in a non-conservative amino acid change located in the coiled-coil domain (IPR012290) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.003 in 1604646 control chromosomes in the gnomAD database, including 12 homozygotes. The observed relatively high frequency together with the homozygous occurrences might indicate a benign nature for the variant. On the other hand, the variant c.323C>G has been reported in the literature in individuals affected with various coagulation disorders, including Hypofibrinogenemia, Dysfibrinogenemia, Thrombocytopenia, Familial multiple coagulation factor deficiencies (FMCFD) with or without a second variant, and also with co-occurring variants in other coagulation genes (e.g. Brennan_2000, Downes_2019, Preisler_2021, Saes_2019, Smith_2018, Couzens_2022, Weronska_2022). These occurrences are inconsistent with an established inheritance pattern (i.e., dominant or recessive) and indicate that the variant may be associated with disease. The variant was found to be present at s relatively high frequency in European populations (0.3%-0.4%) and was associated with only a small estimated effect size on plasma fibrinogen (21.1% lower fibrinogen level per copy of the minor allele) in a GWAS (Huffman_2015), which raises questions about whether it is a causative autosomal dominant variant with variable penetrance and expressivity, an autosomal recessive variant, or a risk-enhancing variant in a possible oligogenic model of inheritance influencing phenotypic heterogeneity Ramanan_2023). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 10688828, 35809055, 31064749, 26105150, 33477601, 37583269, 30431218, 30349899, 35975558). ClinVar contains an entry for this variant (Variation ID: 547969). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Congenital fibrinogen deficiency

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 10, 2021

The FGG c.323C>G (p.Ala108Gly), also known as p.Ala82Gly based on its location in the mature peptide, and "fibrinogen Dunedin" is a recurrent missense variant. Across a selection of the available literature, the p.Ala108Gly has been reported in a heterozygous state in at least 10 individuals, and in a compound heterozygous state in at least one individual, all of whom are reported to have mild-moderate bleeding disorders with or without thromboembolism. This includes four individuals diagnosed with hypofibrinogenemia and one individual diagnosed with hypodysfibrinogenemia (Brennan et al. 2000; Ivaskevicius et al. 2005; Casini et a. 2017; Downes et al. 2019; Wypasek et al. 2019). The p.Ala108Gly variant is reported at a frequency of 0.003603 in the European (non-Finnish) population of the Genome Aggregation Database. This allele frequency is high but is consistent with available disease prevalence and penetrance estimates (Paraboschi et al. 2017). The p.Ala108Gly variant is located in the triple helix region that separates the E and D domains of the protein and it has been suggested that this variant may result in abnormal packing of the helices and defective polymerization, however this has not been confirmed experimentally (Brennan et al. 2000; Casini et a. 2017). Based on the collective evidence and application of the ACMG criteria, the p.Ala108Gly variant is classified as likely pathogenic for congenital fibrinogen deficiency. -

Familial dysfibrinogenemia;C2584774:Congenital afibrinogenemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

PM2_Supporting+PS4+PP4_Moderate -

Thrombus

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

- -

Abnormal bleeding

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Thrombocytopenia;C1458140:Abnormal bleeding

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Birmingham Platelet Group; University of Birmingham

May 01, 2020

- -

FGG-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 03, 2024

The FGG c.323C>G variant is predicted to result in the amino acid substitution p.Ala108Gly. This variant has been reported in patients with hypofibrinogenemia or dysfibrinogenemia, although conclusive evidence of pathogenicity was not presented (legacy nomenclature p.Ala82Gly; Smith et al. 2018. PubMed ID: 30349899; Huffman et al. 2015. PubMedID: 26105150; de Moerloose et al. 2013. PubMed ID: 23852822; Duga et al. 2005. PubMedID 15842357; Brennan et al. 2000. PubMedID: 10688828). This variant is reported in 0.36% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is listed in ClinVar with conflicting interpretations of pathogenicity of pathogenic (1), likely pathogenic (8), and uncertain significance (1) (https://www.ncbi.nlm.nih.gov/clinvar/variation/547969/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Uncertain

0.48

.;.;T;T;T;T

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.71

T;T;T;T;T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.012

T;T;T;T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.3

M;.;M;.;.;.

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.97

N;N;N;N;N;N

REVEL

Uncertain

0.46

Sift

Benign

0.34

T;T;T;T;T;T

Sift4G

Benign

0.34

T;T;T;T;T;T

Polyphen

0.0010

B;B;B;B;.;.

Vest4

0.43

MVP

0.86

MPC

0.34

ClinPred

0.012

GERP RS

5.1

Varity_R

0.19

gMVP

0.34

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

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