rs2070018

Variant names:

• chr4-154587475-G-A
• rs2070018
• NM_021871.4:c.510+37C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-154587475-G-A
• chr4-154587475-G-C
• chr4-154587475-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021871.4(FGA):​c.510+37C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.876 in 1,605,114 control chromosomes in the GnomAD database, including 615,912 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (58579 hom., cov: 30)
  • Exomes 𝑓: 0.88 (557333 hom.)
• Consequence: FGA NM_021871.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.169
• Publications: 17 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 4-154587475-G-A is Benign according to our data. Variant chr4-154587475-G-A is described in ClinVar as Benign. ClinVar VariationId is 1268821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGA	NM_021871.4	c.510+37C>T		intron_variant	Intron 4 of 4	ENST00000403106.8	NP_068657.1
FGA	NM_000508.5	c.510+37C>T		intron_variant	Intron 4 of 5		NP_000499.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGA	ENST00000403106.8	c.510+37C>T		intron_variant	Intron 4 of 4	1	NM_021871.4	ENSP00000385981.3
FGA	ENST00000651975.2	c.510+37C>T		intron_variant	Intron 4 of 5			ENSP00000498441.1
ENSG00000306549	ENST00000819308.1	n.137+711G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.878 AC: 133348 AN: 151900 Hom.: 58534 Cov.: 30

Gnomad AFR AF: 0.895

Gnomad AMI AF: 0.885

Gnomad AMR AF: 0.875

Gnomad ASJ AF: 0.784

Gnomad EAS AF: 0.943

Gnomad SAS AF: 0.859

Gnomad FIN AF: 0.852

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.873

Gnomad OTH AF: 0.885

GnomAD2 exomes AF: 0.873 AC: 219178 AN: 251038 AF XY: 0.873

Gnomad AFR exome AF: 0.894

Gnomad AMR exome AF: 0.860

Gnomad ASJ exome AF: 0.796

Gnomad EAS exome AF: 0.949

Gnomad FIN exome AF: 0.849

Gnomad NFE exome AF: 0.877

Gnomad OTH exome AF: 0.870

GnomAD4 exome AF: 0.875 AC: 1272061 AN: 1453096 Hom.: 557333 Cov.: 28 AF XY: 0.875 AC XY: 633212 AN XY: 723490

African (AFR) AF: 0.898 AC: 29880 AN: 33282

American (AMR) AF: 0.862 AC: 38523 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.794 AC: 20705 AN: 26082

East Asian (EAS) AF: 0.965 AC: 38256 AN: 39630

South Asian (SAS) AF: 0.858 AC: 73878 AN: 86090

European-Finnish (FIN) AF: 0.849 AC: 45215 AN: 53248

Middle Eastern (MID) AF: 0.902 AC: 5187 AN: 5748

European-Non Finnish (NFE) AF: 0.877 AC: 968128 AN: 1104222

Other (OTH) AF: 0.870 AC: 52289 AN: 60098

GnomAD4 genome AF: 0.878 AC: 133450 AN: 152018 Hom.: 58579 Cov.: 30 AF XY: 0.877 AC XY: 65139 AN XY: 74296

African (AFR) AF: 0.895 AC: 37096 AN: 41436

American (AMR) AF: 0.875 AC: 13345 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.784 AC: 2722 AN: 3470

East Asian (EAS) AF: 0.942 AC: 4875 AN: 5174

South Asian (SAS) AF: 0.858 AC: 4132 AN: 4816

European-Finnish (FIN) AF: 0.852 AC: 9001 AN: 10560

Middle Eastern (MID) AF: 0.908 AC: 267 AN: 294

European-Non Finnish (NFE) AF: 0.873 AC: 59344 AN: 68002

Other (OTH) AF: 0.884 AC: 1861 AN: 2106

Alfa AF: 0.872 Hom.: 66583

Bravo AF: 0.882

Asia WGS AF: 0.885 AC: 3078 AN: 3478

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	-0.88
CADD	Benign	0.32
DANN	Benign	0.65
PhyloP100		0.17
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: rs2070018; hg19: chr4-155508627;