4-154563085-T-C

Variant names:

• chr4-154563085-T-C
• rs1368231341
• NM_005141.5:c.67T>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_005141.5(FGB):​c.67T>C​(p.Leu23Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000633 in 1,422,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: FGB NM_005141.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.517
• 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-154563085-T-C is Benign according to our data. Variant chr4-154563085-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2900011.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.517 with no splicing effect.

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.67T>C	p.Leu23Leu	synonymous	Exon 1 of 8	NP_005132.2	P02675
	FGB	NM_001382763.1		c.67T>C	p.Leu23Leu	synonymous	Exon 1 of 8	NP_001369692.1
	FGB	NM_001382765.1		c.67T>C	p.Leu23Leu	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.67T>C	p.Leu23Leu	synonymous	Exon 1 of 8	ENSP00000306099.4	P02675
	FGB	ENST00000497097.5	TSL:1	n.74T>C		non_coding_transcript_exon	Exon 1 of 3
	FGB	ENST00000509493.1	TSL:5	c.-215T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000426757.1	D6REL8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 197940 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000633 AC: 9 AN: 1422666 Hom.: 0 Cov.: 28 AF XY: 0.00000568 AC XY: 4 AN XY: 704322

African (AFR) AF: 0.00 AC: 0 AN: 32560

American (AMR) AF: 0.00 AC: 0 AN: 40726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25540

East Asian (EAS) AF: 0.00 AC: 0 AN: 38024

South Asian (SAS) AF: 0.0000123 AC: 1 AN: 81198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5556

European-Non Finnish (NFE) AF: 0.00000735 AC: 8 AN: 1089128

Other (OTH) AF: 0.00 AC: 0 AN: 58690

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000469 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.8
DANN	Benign	0.69
PhyloP100		-0.52
PromoterAI		0.022	Neutral

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: rs1368231341; hg19: chr4-155484237;