chr4-154604334-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_021870.3(FGG):c.*500C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,510,172 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 1 hom. )

Consequence

FGG
NM_021870.3 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.190

Publications

1 publications found

Variant links:

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

FGG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.001 (152/152054) while in subpopulation NFE AF = 0.00187 (127/67964). AF 95% confidence interval is 0.0016. There are 0 homozygotes in GnomAd4. There are 57 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.*500C>T		3_prime_UTR	Exon 9 of 9	NP_068656.2	P02679-1
	FGG	NM_000509.6		c.*6C>T		3_prime_UTR	Exon 10 of 10	NP_000500.2	P02679-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FGG	ENST00000336098.8	TSL:2 MANE Select	c.*500C>T	3_prime_UTR	Exon 9 of 9	ENSP00000336829.3	P02679-1
FGG	ENST00000404648.7	TSL:1	c.*6C>T	3_prime_UTR	Exon 10 of 10	ENSP00000384860.3	P02679-2
FGG	ENST00000405164.5	TSL:5	c.*6C>T	3_prime_UTR	Exon 10 of 10	ENSP00000384101.1	C9JEU5

Frequencies

GnomAD3 genomes

AF:

0.00100

AC:

152

AN:

151938

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000624

Gnomad FIN

AF:

0.000758

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00187

Gnomad OTH

AF:

0.000959

GnomAD2 exomes

AF:

0.000880

AC:

116

AN:

131812

AF XY:

0.00100

show subpopulations

Gnomad AFR exome

AF:

0.000300

Gnomad AMR exome

AF:

0.000183

Gnomad ASJ exome

AF:

0.000128

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00119

Gnomad NFE exome

AF:

0.00135

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00132

AC:

1796

AN:

1358118

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

870

AN XY:

669326

show subpopulations

African (AFR)

AF:

0.000346

AC:

AN:

28866

American (AMR)

AF:

0.000182

AC:

AN:

27548

Ashkenazi Jewish (ASJ)

AF:

0.0000413

AC:

AN:

24242

East Asian (EAS)

AF:

0.00

AC:

AN:

33884

South Asian (SAS)

AF:

0.000832

AC:

AN:

69698

European-Finnish (FIN)

AF:

0.00140

AC:

AN:

49192

Middle Eastern (MID)

AF:

0.000359

AC:

AN:

5572

European-Non Finnish (NFE)

AF:

0.00150

AC:

1597

AN:

1062792

Other (OTH)

AF:

0.000959

AC:

AN:

56324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.407

Heterozygous variant carriers

129

194

258

323

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00100

AC:

152

AN:

152054

Hom.:

Cov.:

AF XY:

0.000767

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41516

American (AMR)

AF:

0.000131

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000624

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.000758

AC:

AN:

10556

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00187

AC:

127

AN:

67964

Other (OTH)

AF:

0.000949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00109

Hom.:

Bravo

AF:

0.000880

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital afibrinogenemia (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

5.0

(source)

DANN

Benign

0.78

PhyloP100

-0.19

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over