rs1339535578

Variant names:

• chr4-154563132-G-A
• rs1339535578
• NM_005141.5:c.114G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-154563132-G-A
• chr4-154563132-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005141.5(FGB):​c.114G>A​(p.Glu38Glu) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.0000066 in 151,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FGB NM_005141.5 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.12
• Publications: 0 publications found

Genes affected

FGB (HGNC:3662): (fibrinogen beta chain) The protein encoded by this gene is the beta component of fibrinogen, a blood-borne glycoprotein comprised of three pairs of nonidentical polypeptide chains. Following vascular injury, fibrinogen is cleaved by thrombin to form fibrin which is the most abundant component of blood clots. In addition, various cleavage products of fibrinogen and fibrin regulate cell adhesion and spreading, display vasoconstrictor and chemotactic activities, and are mitogens for several cell types. Fibrinogen serves key roles in hemostasis and antimicrobial host defense. Mutations in this gene lead to several disorders, including afibrinogenemia, dysfibrinogenemia, hypodysfibrinogenemia and thrombotic tendency. [provided by RefSeq, Aug 2020]

FGB Gene-Disease associations (from GenCC):

• congenital fibrinogen deficiency

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• thrombophilia

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
• congenital afibrinogenemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• familial dysfibrinogenemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial hypofibrinogenemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005141.5. 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
	FGB	NM_005141.5	MANE Select	c.114G>A	p.Glu38Glu	splice_region synonymous	Exon 1 of 8	NP_005132.2	P02675
	FGB	NM_001382763.1		c.114G>A	p.Glu38Glu	splice_region synonymous	Exon 1 of 8	NP_001369692.1
	FGB	NM_001382765.1		c.114G>A	p.Glu38Glu	splice_region synonymous	Exon 1 of 8	NP_001369694.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGB	ENST00000302068.9	TSL:1 MANE Select	c.114G>A	p.Glu38Glu	splice_region synonymous	Exon 1 of 8	ENSP00000306099.4	P02675
	FGB	ENST00000497097.5	TSL:1	n.121G>A		splice_region non_coding_transcript_exon	Exon 1 of 3
	FGB	ENST00000509493.1	TSL:5	c.-168G>A		splice_region	Exon 1 of 6	ENSP00000426757.1	D6REL8

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151596 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1235032 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 618236

African (AFR) AF: 0.00 AC: 0 AN: 28354

American (AMR) AF: 0.00 AC: 0 AN: 36524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24130

East Asian (EAS) AF: 0.00 AC: 0 AN: 35120

South Asian (SAS) AF: 0.00 AC: 0 AN: 75004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49022

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 929842

Other (OTH) AF: 0.00 AC: 0 AN: 52302

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151596 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73994

African (AFR) AF: 0.00 AC: 0 AN: 41324

American (AMR) AF: 0.00 AC: 0 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67754

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Benign	0.63
PhyloP100		4.1
PromoterAI		-0.018	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.90		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1339535578; hg19: chr4-155484284;