rs2070022

Variant names:

• chr4-154583796-G-A
• rs2070022
• NM_000508.5:c.*328C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000508.5(FGA):​c.*328C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 267,466 control chromosomes in the GnomAD database, including 4,668 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.18 (2673 hom., cov: 32)
  • Exomes 𝑓: 0.17 (1995 hom.)
• Consequence: FGA NM_000508.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.28
• Publications: 23 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGA	NM_000508.5	c.*328C>T		3_prime_UTR_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.*328C>T		3_prime_UTR_variant	Exon 6 of 6			ENSP00000498441.1

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26726 AN: 151962 Hom.: 2664 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.302

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.214

Gnomad MID AF: 0.134

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.182

GnomAD4 exome AF: 0.173 AC: 19919 AN: 115388 Hom.: 1995 Cov.: 0 AF XY: 0.171 AC XY: 10355 AN XY: 60382

African (AFR) AF: 0.117 AC: 400 AN: 3408

American (AMR) AF: 0.312 AC: 1606 AN: 5142

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 483 AN: 3506

East Asian (EAS) AF: 0.128 AC: 805 AN: 6266

South Asian (SAS) AF: 0.181 AC: 2198 AN: 12144

European-Finnish (FIN) AF: 0.210 AC: 1151 AN: 5484

Middle Eastern (MID) AF: 0.161 AC: 79 AN: 490

European-Non Finnish (NFE) AF: 0.167 AC: 12024 AN: 72192

Other (OTH) AF: 0.174 AC: 1173 AN: 6756

GnomAD4 genome AF: 0.176 AC: 26746 AN: 152078 Hom.: 2673 Cov.: 32 AF XY: 0.181 AC XY: 13471 AN XY: 74326

African (AFR) AF: 0.129 AC: 5346 AN: 41482

American (AMR) AF: 0.303 AC: 4618 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 512 AN: 3470

East Asian (EAS) AF: 0.113 AC: 586 AN: 5178

South Asian (SAS) AF: 0.224 AC: 1079 AN: 4822

European-Finnish (FIN) AF: 0.214 AC: 2260 AN: 10556

Middle Eastern (MID) AF: 0.127 AC: 37 AN: 292

European-Non Finnish (NFE) AF: 0.172 AC: 11718 AN: 67994

Other (OTH) AF: 0.188 AC: 396 AN: 2110

Alfa AF: 0.177 Hom.: 4381

Bravo AF: 0.177

Asia WGS AF: 0.182 AC: 632 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	10
DANN	Benign	0.67
PhyloP100		1.3
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: rs2070022; hg19: chr4-155504948; COSMIC: COSV57400052; COSMIC: COSV57400052;