rs2066870

chr4-154610181-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.81

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]

ACMG classification

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	UniProt
FGG	NM_021870.3	c.418T>C	p.Tyr140His	missense_variant	5/9	ENST00000336098.8
FGG	NM_000509.6	c.418T>C	p.Tyr140His	missense_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGG	ENST00000336098.8	c.418T>C	p.Tyr140His	missense_variant	5/9	2	NM_021870.3

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2632 AN: 152146 Hom.: 79 Cov.: 32

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.: 27 AF XY: 0.00341 AC XY: 462 AN XY: 135592

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.: 58 Cov.: 28 AF XY: 0.00162 AC XY: 1160 AN XY: 714272

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.: 79 Cov.: 32 AF XY: 0.0165 AC XY: 1228 AN XY: 74464

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.: 33

Bravo AF: 0.0200

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0561 AC: 247

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00594 AC: 721

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	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) -

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	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	17
Dann	Benign	0.94
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.35	N
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	T
MutationAssessor	Uncertain	2.2	M;.;M;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.54	T
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	T
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

Other links and lift over

dbSNP: rs2066870; hg19: chr4-155531333;