4-154584139-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000508.5(FGA):c.2586C>T(p.Pro862=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0054 in 1,269,898 control chromosomes in the GnomAD database, including 229 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (111 hom., cov: 28)
  • Exomes 𝑓: 0.0030 (118 hom.)
• Consequence: FGA NM_000508.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.17

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 4-154584139-G-A is Benign according to our data. Variant chr4-154584139-G-A is described in ClinVar as [Benign]. Clinvar id is 256329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.17 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGA	NM_000508.5	c.2586C>T	p.Pro862=	synonymous_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGA	ENST00000651975.2	c.2586C>T	p.Pro862=	synonymous_variant	6/6			P1

Frequencies

GnomAD3 genomes AF: 0.0344 AC: 3307 AN: 96046 Hom.: 111 Cov.: 28

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.00189

Gnomad EAS AF: 0.000430

Gnomad SAS AF: 0.000690

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0280

Gnomad NFE AF: 0.000508

Gnomad OTH AF: 0.0299

GnomAD3 exomes AF: 0.00678 AC: 1476 AN: 217590 Hom.: 51 AF XY: 0.00515 AC XY: 609 AN XY: 118332

Gnomad AFR exome AF: 0.0933

Gnomad AMR exome AF: 0.00482

Gnomad ASJ exome AF: 0.00276

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000231

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000426

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00302 AC: 3544 AN: 1173796 Hom.: 118 Cov.: 33 AF XY: 0.00267 AC XY: 1550 AN XY: 579742

Gnomad4 AFR exome AF: 0.105

Gnomad4 AMR exome AF: 0.00614

Gnomad4 ASJ exome AF: 0.00181

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000306

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000266

Gnomad4 OTH exome AF: 0.00831

GnomAD4 genome AF: 0.0345 AC: 3319 AN: 96102 Hom.: 111 Cov.: 28 AF XY: 0.0332 AC XY: 1558 AN XY: 46948

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.0148

Gnomad4 ASJ AF: 0.00189

Gnomad4 EAS AF: 0.000430

Gnomad4 SAS AF: 0.000347

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000509

Gnomad4 OTH AF: 0.0295

Alfa AF: 0.00736 Hom.: 28

Bravo AF: 0.0258

Asia WGS AF: 0.00578 AC: 20 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 13, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.028
Dann	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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

Publications

LitVar

Other links and lift over

dbSNP: rs2070033; hg19: chr4-155505291;