4-154584137-AG-A

Variant names:

• chr4-154584137-AG-A
• rs773678959
• NM_000508.5:c.2587delC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PVS1_Moderate BP6_Moderate

The NM_000508.5(FGA):​c.2587delC​(p.Val864fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000483 in 1,242,112 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: FGA NM_000508.5 frameshift
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.119
• Publications: 1 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: Uncertain_significance. The variant received 0 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. Fraction of 0.00538 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BP6: Variant 4-154584137-AG-A is Benign according to our data. Variant chr4-154584137-AG-A is described in ClinVar as [Benign]. Clinvar id is 802094.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGA	NM_000508.5	c.2587delC	p.Val864fs	frameshift_variant	Exon 6 of 6		NP_000499.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGA	ENST00000651975.2	c.2587delC	p.Val864fs	frameshift_variant	Exon 6 of 6			ENSP00000498441.1

Frequencies

GnomAD3 genomes AF: 0.0000214 AC: 2 AN: 93244 Hom.: 0 Cov.: 28

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: 0.0000224

Gnomad OTH AF: 0.000751

GnomAD2 exomes AF: 0.0000141 AC: 3 AN: 212378 AF XY: 0.00000866

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: 0.0000303

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000348 AC: 4 AN: 1148868 Hom.: 0 Cov.: 33 AF XY: 0.00000352 AC XY: 2 AN XY: 567802

African (AFR) AF: 0.00 AC: 0 AN: 24012

American (AMR) AF: 0.00 AC: 0 AN: 32736

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21294

East Asian (EAS) AF: 0.00 AC: 0 AN: 24440

South Asian (SAS) AF: 0.00 AC: 0 AN: 57630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39808

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4578

European-Non Finnish (NFE) AF: 0.00000446 AC: 4 AN: 897006

Other (OTH) AF: 0.00 AC: 0 AN: 47364

GnomAD4 genome AF: 0.0000214 AC: 2 AN: 93244 Hom.: 0 Cov.: 28 AF XY: 0.0000219 AC XY: 1 AN XY: 45572

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22074

American (AMR) AF: 0.00 AC: 0 AN: 10176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2634

East Asian (EAS) AF: 0.00 AC: 0 AN: 2302

South Asian (SAS) AF: 0.00 AC: 0 AN: 2880

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 212

European-Non Finnish (NFE) AF: 0.0000224 AC: 1 AN: 44738

Other (OTH) AF: 0.000751 AC: 1 AN: 1332

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.006664), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial visceral amyloidosis, Ostertag type Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.12
Mutation Taster		=29/171	disease causing

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: rs773678959; hg19: chr4-155505289;