4-154590745-T-C

Variant names:

• chr4-154590745-T-C
• rs2070011
• ENST00000819308.1:n.138-2183T>C

Variant summary

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

The ENST00000819308.1(ENSG00000306549):​n.138-2183T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.624 in 1,283,734 control chromosomes in the GnomAD database, including 251,421 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32380 hom., cov: 33)
  • Exomes 𝑓: 0.62 (219041 hom.)
• Consequence: ENSG00000306549 ENST00000819308.1 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.704
• Publications: 45 publications found

Genes affected

ENSG00000306549 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-154590745-T-C is Benign according to our data. Variant chr4-154590745-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 347824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGA	NM_021871.4	c.-58A>G		upstream_gene_variant		ENST00000403106.8	NP_068657.1
FGA	NM_000508.5	c.-58A>G		upstream_gene_variant			NP_000499.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000306549	ENST00000819308.1	n.138-2183T>C		intron_variant	Intron 1 of 1
FGA	ENST00000403106.8	c.-58A>G		upstream_gene_variant		1	NM_021871.4	ENSP00000385981.3
FGA	ENST00000651975.2	c.-58A>G		upstream_gene_variant				ENSP00000498441.1

Frequencies

GnomAD3 genomes AF: 0.648 AC: 98541 AN: 152022 Hom.: 32342 Cov.: 33

Gnomad AFR AF: 0.745

Gnomad AMI AF: 0.629

Gnomad AMR AF: 0.649

Gnomad ASJ AF: 0.686

Gnomad EAS AF: 0.501

Gnomad SAS AF: 0.556

Gnomad FIN AF: 0.540

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.621

Gnomad OTH AF: 0.674

GnomAD4 exome AF: 0.620 AC: 702012 AN: 1131594 Hom.: 219041 Cov.: 15 AF XY: 0.617 AC XY: 351984 AN XY: 570406

African (AFR) AF: 0.752 AC: 19761 AN: 26280

American (AMR) AF: 0.634 AC: 22425 AN: 35368

Ashkenazi Jewish (ASJ) AF: 0.677 AC: 15932 AN: 23540

East Asian (EAS) AF: 0.499 AC: 17198 AN: 34432

South Asian (SAS) AF: 0.533 AC: 39313 AN: 73794

European-Finnish (FIN) AF: 0.532 AC: 26089 AN: 49054

Middle Eastern (MID) AF: 0.699 AC: 3639 AN: 5208

European-Non Finnish (NFE) AF: 0.630 AC: 526182 AN: 834840

Other (OTH) AF: 0.641 AC: 31473 AN: 49078

GnomAD4 genome AF: 0.648 AC: 98635 AN: 152140 Hom.: 32380 Cov.: 33 AF XY: 0.643 AC XY: 47807 AN XY: 74362

African (AFR) AF: 0.745 AC: 30960 AN: 41532

American (AMR) AF: 0.650 AC: 9927 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.686 AC: 2379 AN: 3470

East Asian (EAS) AF: 0.501 AC: 2585 AN: 5162

South Asian (SAS) AF: 0.554 AC: 2673 AN: 4822

European-Finnish (FIN) AF: 0.540 AC: 5721 AN: 10588

Middle Eastern (MID) AF: 0.707 AC: 208 AN: 294

European-Non Finnish (NFE) AF: 0.621 AC: 42184 AN: 67964

Other (OTH) AF: 0.674 AC: 1424 AN: 2112

Alfa AF: 0.633 Hom.: 114135

Bravo AF: 0.660

Asia WGS AF: 0.580 AC: 2019 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

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

- -

Feb 03, 2025

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Congenital afibrinogenemia Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Familial visceral amyloidosis, Ostertag type Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.9
DANN	Benign	0.63
PhyloP100		-0.70
PromoterAI		-0.0038	Neutral
Mutation Taster		=114/186	disease causing (long InDel)

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: rs2070011; hg19: chr4-155511897; COSMIC: COSV57394259; COSMIC: COSV57394259;