4-154585806-GA-G

Variant names:

• chr4-154585806-GA-G
• rs587777761
• NM_021871.4:c.1622delT

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_021871.4(FGA):​c.1622delT​(p.Val541AlafsTer27) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGA NM_021871.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.791
• Publications: 5 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• congenital afibrinogenemia

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

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

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

  Inheritance: AR, AD 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: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-154585806-GA-G is Pathogenic according to our data. Variant chr4-154585806-GA-G is described in CliVar as Pathogenic. Clinvar id is 16409.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-154585806-GA-G is described in CliVar as Pathogenic. Clinvar id is 16409.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-154585806-GA-G is described in CliVar as Pathogenic. Clinvar id is 16409.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-154585806-GA-G is described in CliVar as Pathogenic. Clinvar id is 16409.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-154585806-GA-G is described in CliVar as Pathogenic. Clinvar id is 16409.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-154585806-GA-G is described in CliVar as Pathogenic. Clinvar id is 16409.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-154585806-GA-G is described in CliVar as Pathogenic. Clinvar id is 16409.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-154585806-GA-G is described in CliVar as Pathogenic. Clinvar id is 16409.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGA	NM_021871.4	c.1622delT	p.Val541AlafsTer27	frameshift_variant	Exon 5 of 5	ENST00000403106.8	NP_068657.1
FGA	NM_000508.5	c.1622delT	p.Val541AlafsTer27	frameshift_variant	Exon 5 of 6		NP_000499.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGA	ENST00000403106.8	c.1622delT	p.Val541AlafsTer27	frameshift_variant	Exon 5 of 5	1	NM_021871.4	ENSP00000385981.3
FGA	ENST00000651975.2	c.1622delT	p.Val541AlafsTer27	frameshift_variant	Exon 5 of 6			ENSP00000498441.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Familial visceral amyloidosis, Ostertag type Pathogenic:1

Dec 15, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.79
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs587777761; hg19: chr4-155506958;