rs2070016

Variant names:

• chr4-154589162-A-G
• rs2070016
• NM_021871.4:c.181-186T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_021871.4(FGA):​c.181-186T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 152,108 control chromosomes in the GnomAD database, including 1,343 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.12 (1343 hom., cov: 32)
• Consequence: FGA NM_021871.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.05
• Publications: 22 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

ENSG00000306549 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-154589162-A-G is Benign according to our data. Variant chr4-154589162-A-G is described in ClinVar as Benign. ClinVar VariationId is 1279619.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021871.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGA	NM_021871.4	MANE Select	c.181-186T>C		intron	N/A	NP_068657.1
	FGA	NM_000508.5		c.181-186T>C		intron	N/A	NP_000499.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGA	ENST00000403106.8	TSL:1 MANE Select	c.181-186T>C		intron	N/A	ENSP00000385981.3
	FGA	ENST00000651975.2		c.181-186T>C		intron	N/A	ENSP00000498441.1
	ENSG00000306549	ENST00000819308.1		n.137+2398A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18654 AN: 151990 Hom.: 1341 Cov.: 32

Gnomad AFR AF: 0.0540

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.141

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.123 AC: 18658 AN: 152108 Hom.: 1343 Cov.: 32 AF XY: 0.122 AC XY: 9051 AN XY: 74374

African (AFR) AF: 0.0540 AC: 2241 AN: 41502

American (AMR) AF: 0.110 AC: 1676 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 820 AN: 3470

East Asian (EAS) AF: 0.208 AC: 1078 AN: 5172

South Asian (SAS) AF: 0.137 AC: 660 AN: 4802

European-Finnish (FIN) AF: 0.134 AC: 1417 AN: 10592

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.151 AC: 10271 AN: 67972

Other (OTH) AF: 0.139 AC: 293 AN: 2108

Alfa AF: 0.146 Hom.: 5856

Bravo AF: 0.120

Asia WGS AF: 0.151 AC: 526 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.40
DANN	Benign	0.37
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs2070016; hg19: chr4-155510314;