4-154590672-T-C

Variant names:

• chr4-154590672-T-C
• rs2070025
• NM_021871.4:c.16A>G

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.16A>G​(p.Ile6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,557,848 control chromosomes in the GnomAD database, including 193 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (176 hom.)
• Consequence: FGA NM_021871.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0180
• Publications: 10 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 (MetaRNN=0.0013471544).
• BP6: Variant 4-154590672-T-C is Benign according to our data. Variant chr4-154590672-T-C is described in ClinVar as Benign. ClinVar VariationId is 347823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0796 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.16A>G	p.Ile6Val	missense	Exon 1 of 5	NP_068657.1
	FGA	NM_000508.5		c.16A>G	p.Ile6Val	missense	Exon 1 of 6	NP_000499.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGA	ENST00000403106.8	TSL:1 MANE Select	c.16A>G	p.Ile6Val	missense	Exon 1 of 5	ENSP00000385981.3
	FGA	ENST00000651975.2		c.16A>G	p.Ile6Val	missense	Exon 1 of 6	ENSP00000498441.1
	FGA	ENST00000951263.1		c.16A>G	p.Ile6Val	missense	Exon 1 of 6	ENSP00000621322.1

Frequencies

GnomAD3 genomes AF: 0.00349 AC: 531 AN: 152214 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0856

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00764 AC: 1264 AN: 165434 AF XY: 0.00708

Gnomad AFR exome AF: 0.00112

Gnomad AMR exome AF: 0.000238

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.0969

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000759

Gnomad OTH exome AF: 0.00545

GnomAD4 exome AF: 0.00273 AC: 3837 AN: 1405516 Hom.: 176 Cov.: 30 AF XY: 0.00256 AC XY: 1775 AN XY: 693736

African (AFR) AF: 0.000436 AC: 14 AN: 32120

American (AMR) AF: 0.000193 AC: 7 AN: 36246

Ashkenazi Jewish (ASJ) AF: 0.000277 AC: 7 AN: 25226

East Asian (EAS) AF: 0.0876 AC: 3204 AN: 36590

South Asian (SAS) AF: 0.000992 AC: 79 AN: 79620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49734

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5704

European-Non Finnish (NFE) AF: 0.0000379 AC: 41 AN: 1081940

Other (OTH) AF: 0.00830 AC: 484 AN: 58336

GnomAD4 genome AF: 0.00351 AC: 534 AN: 152332 Hom.: 17 Cov.: 32 AF XY: 0.00400 AC XY: 298 AN XY: 74488

African (AFR) AF: 0.00106 AC: 44 AN: 41578

American (AMR) AF: 0.00124 AC: 19 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.0862 AC: 446 AN: 5176

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68032

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00263 Hom.: 42

Bravo AF: 0.00384

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00481 AC: 537

Asia WGS AF: 0.0470 AC: 164 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Congenital afibrinogenemia (1)
-	-	1	Familial visceral amyloidosis, Ostertag type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.0
DANN	Benign	0.83
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.018
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.036
Sift	Benign	0.52	T
Sift4G	Benign	0.60	T
Polyphen		0.051	B
Vest4		0.028
MVP		0.17
MPC		0.055
ClinPred		0.0016	T
GERP RS		0.59
PromoterAI		-0.11	Neutral
Varity_R		0.019
gMVP		0.12
Mutation Taster		=98/2	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: rs2070025; hg19: chr4-155511824; COSMIC: COSV107388304;