4-154589514-G-C

Variant names:

• chr4-154589514-G-C
• NM_021871.4:c.103C>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_021871.4(FGA):​c.103C>G​(p.Arg35Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). 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)
• Consequence: FGA NM_021871.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 6.58

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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, 0.793

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGA	NM_021871.4	c.103C>G	p.Arg35Gly	missense_variant	Exon 2 of 5	ENST00000403106.8	NP_068657.1
FGA	NM_000508.5	c.103C>G	p.Arg35Gly	missense_variant	Exon 2 of 6		NP_000499.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGA	ENST00000403106.8	c.103C>G	p.Arg35Gly	missense_variant	Exon 2 of 5	1	NM_021871.4	ENSP00000385981.3
FGA	ENST00000651975.2	c.103C>G	p.Arg35Gly	missense_variant	Exon 2 of 6			ENSP00000498441.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Afibrinogenemia Pathogenic:1

-

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Familial dysfibrinogenemia Uncertain:1

-

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.7	M;M;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.6	D;D;.
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.79
MutPred		0.43		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		0.83
MPC		0.13
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.95
gMVP		0.67

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-155510666;