rs2066870

Positions:

chr4-154610181-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_021870.3(FGG):c.418T>C(p.Tyr140His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00335 in 1,584,110 control chromosomes in the GnomAD database, including 137 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 79 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 58 hom. )

Consequence

FGG
NM_021870.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.81

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024793744).

BP6

Variant 4-154610181-A-G is Benign according to our data. Variant chr4-154610181-A-G is described in ClinVar as [Benign]. Clinvar id is 347830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0581 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGG	NM_021870.3 linkuse as main transcript	c.418T>C	p.Tyr140His	missense_variant	5/9	ENST00000336098.8	NP_068656.2
FGG	NM_000509.6 linkuse as main transcript	c.418T>C	p.Tyr140His	missense_variant	5/10		NP_000500.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGG	ENST00000336098.8 linkuse as main transcript	c.418T>C	p.Tyr140His	missense_variant	5/9	2	NM_021870.3	ENSP00000336829		P02679-1

Frequencies

GnomAD3 genomes

AF:

0.0173

AC:

2632

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0602

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00576

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.00474

AC:

1189

AN:

250840

Hom.:

AF XY:

0.00341

AC XY:

462

AN XY:

135592

show subpopulations

Gnomad AFR exome

AF:

0.0630

Gnomad AMR exome

AF:

0.00305

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000291

Gnomad OTH exome

AF:

0.00426

GnomAD4 exome

AF:

0.00187

AC:

2680

AN:

1431846

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

1160

AN XY:

714272

show subpopulations

Gnomad4 AFR exome

AF:

0.0611

Gnomad4 AMR exome

AF:

0.00350

Gnomad4 ASJ exome

AF:

0.0000386

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000105

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000239

Gnomad4 OTH exome

AF:

0.00399

GnomAD4 genome

AF:

0.0173

AC:

2631

AN:

152264

Hom.:

Cov.:

AF XY:

0.0165

AC XY:

1228

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0600

Gnomad4 AMR

AF:

0.00569

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.00373

Hom.:

Bravo

AF:

0.0200

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.0561

AC:

247

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00594

AC:

721

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2021	This variant is associated with the following publications: (PMID: 27884173, 19420351, 23467727) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Congenital afibrinogenemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.41

.;.;T;T;T;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.79

T;T;T;T;T;T

MetaRNN

Benign

0.0025

T;T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.2

M;.;M;.;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.5

N;N;N;N;N;N

REVEL

Benign

0.26

Sift

Benign

0.17

T;T;T;T;T;T

Sift4G

Benign

0.41

T;T;T;T;T;T

Polyphen

0.013

B;B;B;B;.;.

Vest4

0.064

MVP

0.76

MPC

0.29

ClinPred

0.023

GERP RS

5.7

Varity_R

0.26

gMVP

0.61

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over