rs2070017

Positions:

• chr4-154589124-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021871.4(FGA):​c.181-148G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00973 in 741,652 control chromosomes in the GnomAD database, including 384 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (262 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (122 hom.)
• Consequence: FGA NM_021871.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.451

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-154589124-C-T is Benign according to our data. Variant chr4-154589124-C-T is described in ClinVar as [Benign]. Clinvar id is 1222924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGA	NM_021871.4	c.181-148G>A		intron_variant		ENST00000403106.8	NP_068657.1
FGA	NM_000508.5	c.181-148G>A		intron_variant			NP_000499.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGA	ENST00000403106.8	c.181-148G>A		intron_variant		1	NM_021871.4	ENSP00000385981
FGA	ENST00000651975.2	c.181-148G>A		intron_variant				ENSP00000498441	P1

Frequencies

GnomAD3 genomes AF: 0.0316 AC: 4805 AN: 151986 Hom.: 259 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.0301

GnomAD4 exome AF: 0.00405 AC: 2389 AN: 589548 Hom.: 122 AF XY: 0.00364 AC XY: 1138 AN XY: 312456

Gnomad4 AFR exome AF: 0.108

Gnomad4 AMR exome AF: 0.00704

Gnomad4 ASJ exome AF: 0.00788

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000280

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000412

Gnomad4 OTH exome AF: 0.00986

GnomAD4 genome AF: 0.0317 AC: 4828 AN: 152104 Hom.: 262 Cov.: 32 AF XY: 0.0302 AC XY: 2244 AN XY: 74362

Gnomad4 AFR AF: 0.109

Gnomad4 AMR AF: 0.0108

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.0185 Hom.: 13

Bravo AF: 0.0360

Asia WGS AF: 0.00837 AC: 30 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.8
DANN	Benign	0.60

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: rs2070017; hg19: chr4-155510276;