4-154604338-T-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_021870.3(FGG):c.*496A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,515,318 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (9 hom.)
• Consequence: FGG NM_021870.3 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.510

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 4-154604338-T-G is Benign according to our data. Variant chr4-154604338-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 902205.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High Homozygotes in GnomAd at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGG	NM_021870.3	c.*496A>C		3_prime_UTR_variant	9/9	ENST00000336098.8
FGG	NM_000509.6	c.*2A>C		3_prime_UTR_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGG	ENST00000336098.8	c.*496A>C		3_prime_UTR_variant	9/9	2	NM_021870.3

Frequencies

GnomAD3 genomes AF: 0.00262 AC: 399 AN: 152222 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00409

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00172 AC: 231 AN: 133930 Hom.: 0 AF XY: 0.00195 AC XY: 138 AN XY: 70946

Gnomad AFR exome AF: 0.000865

Gnomad AMR exome AF: 0.00132

Gnomad ASJ exome AF: 0.00102

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000410

Gnomad FIN exome AF: 0.000357

Gnomad NFE exome AF: 0.00300

Gnomad OTH exome AF: 0.00355

GnomAD4 exome AF: 0.00319 AC: 4344 AN: 1362978 Hom.: 9 Cov.: 27 AF XY: 0.00311 AC XY: 2090 AN XY: 671928

Gnomad4 AFR exome AF: 0.000550

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.000985

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000538

Gnomad4 FIN exome AF: 0.000568

Gnomad4 NFE exome AF: 0.00378

Gnomad4 OTH exome AF: 0.00240

GnomAD4 genome AF: 0.00261 AC: 398 AN: 152340 Hom.: 2 Cov.: 32 AF XY: 0.00231 AC XY: 172 AN XY: 74492

Gnomad4 AFR AF: 0.000625

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00409

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00294 Hom.: 1

Bravo AF: 0.00308

Asia WGS AF: 0.000579 AC: 2 AN: 3470

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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. -

FGG-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 02, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
Cadd	Benign	17
Dann	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs187316301; hg19: chr4-155525490;