4-154604334-G-A

Position:

• chr4-154604334-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.190

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGG	NM_021870.3	c.*500C>T		3_prime_UTR_variant	9/9	ENST00000336098.8	NP_068656.2
FGG	NM_000509.6	c.*6C>T		3_prime_UTR_variant	10/10		NP_000500.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGG	ENST00000336098.8	c.*500C>T		3_prime_UTR_variant	9/9	2	NM_021870.3	ENSP00000336829

Frequencies

GnomAD3 genomes AF: 0.00100 AC: 152 AN: 151938 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000880 AC: 116 AN: 131812 Hom.: 0 AF XY: 0.00100 AC XY: 70 AN XY: 69854

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 SAS exome AF: 0.000890

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.: 1 Cov.: 27 AF XY: 0.00130 AC XY: 870 AN XY: 669326

Gnomad4 AFR exome AF: 0.000346

Gnomad4 AMR exome AF: 0.000182

Gnomad4 ASJ exome AF: 0.0000413

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000832

Gnomad4 FIN exome AF: 0.00140

Gnomad4 NFE exome AF: 0.00150

Gnomad4 OTH exome AF: 0.000959

GnomAD4 genome AF: 0.00100 AC: 152 AN: 152054 Hom.: 0 Cov.: 32 AF XY: 0.000767 AC XY: 57 AN XY: 74346

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000624

Gnomad4 FIN AF: 0.000758

Gnomad4 NFE AF: 0.00187

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.00127 Hom.: 0

Bravo AF: 0.000880

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 12, 2023

Variant summary: FGG c.*500C>T is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 0.00088 in 131812 control chromosomes. To our knowledge, no occurrence of c.*500C>T in individuals affected with Congenital Dysfibrinogenemia and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Congenital afibrinogenemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.0
DANN	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs183036893; hg19: chr4-155525486;