rs121913088

Variant names:

• chr4-154606932-C-T
• rs121913088
• NM_021870.3:c.902G>A
• FGG p.Arg301His

Your query was ambiguous. Multiple possible variants found:

• chr4-154606932-C-T
• chr4-154606932-C-G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM5 PP3_Moderate PP5_Very_Strong

The NM_021870.3(FGG):​c.902G>A​(p.Arg301His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003840805: Published functional studies suggest a damaging effect (PMID:20508898)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R301C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: FGG NM_021870.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 7.67
• Publications: 21 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)
• 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 hypofibrinogenemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003840805: Published functional studies suggest a damaging effect (PMID: 20508898); SCV005418775: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-154606933-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936
• PP5: Variant 4-154606932-C-T is Pathogenic according to our data. Variant chr4-154606932-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.902G>A	p.Arg301His	missense	Exon 8 of 9	NP_068656.2	P02679-1
	FGG	NM_000509.6		c.902G>A	p.Arg301His	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.902G>A	p.Arg301His	missense	Exon 8 of 9	ENSP00000336829.3	P02679-1
	FGG	ENST00000404648.7	TSL:1	c.902G>A	p.Arg301His	missense	Exon 8 of 10	ENSP00000384860.3	P02679-2
	FGG	ENST00000407946.5	TSL:5	c.926G>A	p.Arg309His	missense	Exon 8 of 9	ENSP00000384552.1	C9JC84

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152128 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000800 AC: 2 AN: 250136 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461026 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726788

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.0000224 AC: 1 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86144

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111460

Other (OTH) AF: 0.0000166 AC: 1 AN: 60362

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74448

African (AFR) AF: 0.00 AC: 0 AN: 41550

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000140 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Familial dysfibrinogenemia (4)
4	-	-	not provided (4)
1	-	-	Congenital afibrinogenemia (1)
1	-	-	Familial dysfibrinogenemia;C2584774:Congenital afibrinogenemia (1)
1	-	-	Hypofibrinogenemia (1)
-	-	-	FIBRINOGEN HAIFA 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		7.7
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.81
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs121913088;

hg19: chr4-155528084;

COSMIC: COSV60196181;

COSMIC: COSV60196181;