rs121913094

Variant names:

• chr4-154606767-T-A
• rs121913094
• NM_021870.3:c.1067A>T
• FGG p.Asp356Val

Your query was ambiguous. Multiple possible variants found:

• chr4-154606767-T-A
• chr4-154606767-T-C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_021870.3(FGG):​c.1067A>T​(p.Asp356Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D356G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FGG NM_021870.3 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 7.78
• Publications: 2 publications found

Genes affected

FGG (HGNC:3694): (fibrinogen gamma chain) The protein encoded by this gene is the gamma 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. Mutations in this gene lead to several disorders, including dysfibrinogenemia, hypofibrinogenemia and thrombophilia. Alternative splicing results in transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

FGG Gene-Disease associations (from GenCC):

• congenital fibrinogen deficiency

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• familial dysfibrinogenemia

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• congenital afibrinogenemia

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

  Inheritance: AR, AD Classification: STRONG Submitted by: Genomics England PanelApp
• familial hypofibrinogenemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_021870.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-154606767-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2664006.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021870.3. 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
	FGG	NM_021870.3	MANE Select	c.1067A>T	p.Asp356Val	missense	Exon 8 of 9	NP_068656.2	P02679-1
	FGG	NM_000509.6		c.1067A>T	p.Asp356Val	missense	Exon 8 of 10	NP_000500.2	P02679-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGG	ENST00000336098.8	TSL:2 MANE Select	c.1067A>T	p.Asp356Val	missense	Exon 8 of 9	ENSP00000336829.3	P02679-1
	FGG	ENST00000404648.7	TSL:1	c.1067A>T	p.Asp356Val	missense	Exon 8 of 10	ENSP00000384860.3	P02679-2
	FGG	ENST00000407946.5	TSL:5	c.1091A>T	p.Asp364Val	missense	Exon 8 of 9	ENSP00000384552.1	C9JC84

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: other

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	FIBRINOGEN MILANO 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	1.9	M
PhyloP100		7.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.017	D
Sift4G	Benign	0.21	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.97
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs121913094;

hg19: chr4-155527919;