rs121913088

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong

The NM_021870.3(FGG):​c.902G>A​(p.Arg301His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R301C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

FGG
NM_021870.3 missense

Scores

10
8
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 7.67
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr4-154606933-G-A is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.936
PP5
Variant 4-154606932-C-T is Pathogenic according to our data. Variant chr4-154606932-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FGGNM_021870.3 linkuse as main transcriptc.902G>A p.Arg301His missense_variant 8/9 ENST00000336098.8 NP_068656.2
FGGNM_000509.6 linkuse as main transcriptc.902G>A p.Arg301His missense_variant 8/10 NP_000500.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FGGENST00000336098.8 linkuse as main transcriptc.902G>A p.Arg301His missense_variant 8/92 NM_021870.3 ENSP00000336829 P02679-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152128
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000800
AC:
2
AN:
250136
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135184
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000885
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461026
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
726788
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152246
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74448
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial dysfibrinogenemia Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingGenetics and Molecular Pathology, SA PathologyOct 01, 2021- -
Pathogenic, criteria provided, single submitterclinical testingISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology-- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 21, 2024Variant summary: FGG c.902G>A (p.Arg301His) results in a non-conservative amino acid change located in the Fibrinogen, alpha/beta/gamma chain, C-terminal globular domain (IPR002181) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250136 control chromosomes. c.902G>A has been reported in the literature in multiple individuals affected with Dysfibrinogenemia (examples: Smith_2018 and Wang_2018). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.901C>T, p.Arg301Cys), supporting the critical relevance of codon 301 to FGG protein function. The following publications have been ascertained in the context of this evaluation (PMID: 30349899, 29351094). ClinVar contains an entry for this variant (Variation ID: 16362). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJul 14, 2023- -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGeneDxJul 23, 2024Published functional studies suggest a damaging effect (PMID: 20508898); Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.R275H; This variant is associated with the following publications: (PMID: 23683413, 30512152, 36964972, 34455742, 35063457, 7654933, 19132250, 3563970, 1455400, 2958955, 17604827, 30349899, 20546853, 30856382, 34355501, 29351094, 32877852, 20508898, 31064749) -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJul 11, 2022PP3, PP5, PM1, PM2, PM5, PS3, PS4_moderate -
Hypofibrinogenemia Pathogenic:1
Pathogenic, criteria provided, single submitterresearchNIHR Bioresource Rare Diseases, University of CambridgeFeb 01, 2019- -
FIBRINOGEN HAIFA 1 Other:1
other, no assertion criteria providedliterature onlyOMIMSep 19, 2014- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.41
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.48
.;.;T;T
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.91
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D;D;D;D
M_CAP
Pathogenic
0.36
D
MetaRNN
Pathogenic
0.94
D;D;D;D
MetaSVM
Uncertain
0.62
D
MutationAssessor
Pathogenic
3.5
H;.;H;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.56
T
PROVEAN
Uncertain
-2.5
D;D;D;D
REVEL
Pathogenic
0.83
Sift
Uncertain
0.0020
D;D;D;D
Sift4G
Uncertain
0.0060
D;D;D;D
Polyphen
1.0
D;D;D;D
Vest4
0.92
MutPred
0.80
.;Loss of sheet (P = 0.0357);.;Loss of sheet (P = 0.0357);
MVP
0.95
MPC
0.90
ClinPred
1.0
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.90
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs121913088; hg19: chr4-155528084; COSMIC: COSV60196181; COSMIC: COSV60196181; API