rs1316252409

Variant names:

• chr4-154584233-T-C
• rs1316252409
• NM_000508.5:c.2492A>G

Your query was ambiguous. Multiple possible variants found:

• chr4-154584233-T-C
• chr4-154584233-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000508.5(FGA):​c.2492A>G​(p.Asn831Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: FGA NM_000508.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.08
• Publications: 0 publications found

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]

FGA Gene-Disease associations (from GenCC):

• familial dysfibrinogenemia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• congenital afibrinogenemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital fibrinogen deficiency

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• familial visceral amyloidosis

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• thrombophilia

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
• AFib amyloidosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial hypofibrinogenemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15972671).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000508.5. 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
	FGA	NM_000508.5		c.2492A>G	p.Asn831Ser	missense	Exon 6 of 6	NP_000499.1	P02671-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGA	ENST00000651975.2		c.2492A>G	p.Asn831Ser	missense	Exon 6 of 6	ENSP00000498441.1	P02671-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250996 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461730 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727186

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111876

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Benign	0.87
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.16	T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	0.77	N
PhyloP100		2.1
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.23
Sift	Benign	0.046	D
Sift4G	Benign	0.31	T
Polyphen		0.12	B
Vest4		0.036
MutPred		0.29		Gain of glycosylation at Y835 (P = 0.05)
MVP		0.97
MPC		0.064
ClinPred		0.087	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.19
gMVP		0.41
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs1316252409; hg19: chr4-155505385;