4-154589514-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP3PP5_Moderate

The NM_021871.4(FGA):​c.103C>A​(p.Arg35Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,578 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. R35H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FGA
NM_021871.4 missense

Scores

9
8
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.58
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr4-154589513-C-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.782
PP5
Variant 4-154589514-G-T is Pathogenic according to our data. Variant chr4-154589514-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 627196.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FGANM_021871.4 linkc.103C>A p.Arg35Ser missense_variant Exon 2 of 5 ENST00000403106.8 NP_068657.1 P02671-2
FGANM_000508.5 linkc.103C>A p.Arg35Ser missense_variant Exon 2 of 6 NP_000499.1 P02671-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FGAENST00000403106.8 linkc.103C>A p.Arg35Ser missense_variant Exon 2 of 5 1 NM_021871.4 ENSP00000385981.3 P02671-2
FGAENST00000651975.2 linkc.103C>A p.Arg35Ser missense_variant Exon 2 of 6 ENSP00000498441.1 P02671-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461578
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727120
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hypofibrinogenemia Pathogenic:1
Pathogenic, criteria provided, single submitterresearchNIHR Bioresource Rare Diseases, University of CambridgeFeb 01, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.29
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.89
D;.;.
Eigen
Pathogenic
0.72
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.79
T;T;T
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.78
D;D;D
MetaSVM
Uncertain
0.26
D
MutationAssessor
Uncertain
2.7
M;M;.
PrimateAI
Uncertain
0.50
T
PROVEAN
Uncertain
-3.9
D;D;.
REVEL
Uncertain
0.49
Sift
Pathogenic
0.0
D;D;.
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;D;.
Vest4
0.79
MutPred
0.45
Loss of methylation at R35 (P = 0.0239);Loss of methylation at R35 (P = 0.0239);Loss of methylation at R35 (P = 0.0239);
MVP
0.90
MPC
0.15
ClinPred
1.0
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.98
gMVP
0.68

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.

Other links and lift over

dbSNP: rs121909606; hg19: chr4-155510666; API