NM_021871.4:c.181-148G>A

Variant names:

• chr4-154589124-C-T
• rs2070017
• NM_021871.4:c.181-148G>A

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.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
• Publications: 2 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=-0.83).
• BP6: Variant 4-154589124-C-T is Benign according to our data. Variant chr4-154589124-C-T is described in ClinVar as Benign. ClinVar VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGA	NM_021871.4	MANE Select	c.181-148G>A		intron	N/A	NP_068657.1
	FGA	NM_000508.5		c.181-148G>A		intron	N/A	NP_000499.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGA	ENST00000403106.8	TSL:1 MANE Select	c.181-148G>A		intron	N/A	ENSP00000385981.3
	FGA	ENST00000651975.2		c.181-148G>A		intron	N/A	ENSP00000498441.1
	FGA	ENST00000951263.1		c.247-148G>A		intron	N/A	ENSP00000621322.1

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

African (AFR) AF: 0.108 AC: 1594 AN: 14814

American (AMR) AF: 0.00704 AC: 174 AN: 24700

Ashkenazi Jewish (ASJ) AF: 0.00788 AC: 134 AN: 17014

East Asian (EAS) AF: 0.00 AC: 0 AN: 32110

South Asian (SAS) AF: 0.000280 AC: 15 AN: 53638

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45428

Middle Eastern (MID) AF: 0.00682 AC: 16 AN: 2346

European-Non Finnish (NFE) AF: 0.000412 AC: 152 AN: 368662

Other (OTH) AF: 0.00986 AC: 304 AN: 30836

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

African (AFR) AF: 0.109 AC: 4531 AN: 41462

American (AMR) AF: 0.0108 AC: 165 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68014

Other (OTH) AF: 0.0298 AC: 63 AN: 2114

Alfa AF: 0.0185 Hom.: 13

Bravo AF: 0.0360

Asia WGS AF: 0.00837 AC: 30 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.8
DANN	Benign	0.60
PhyloP100		-0.45
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: rs2070017; hg19: chr4-155510276;