rs191297318

Variant names:

• chr4-154604346-G-A
• rs191297318
• ENST00000404648.7:c.1308C>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000509.6(FGG):​c.1308C>T​(p.Asp436Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00231 in 1,510,082 control chromosomes in the GnomAD database, including 100 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 0.0042 (18 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (82 hom.)
• Consequence: FGG NM_000509.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.393

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 4-154604346-G-A is Benign according to our data. Variant chr4-154604346-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 347825.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=0.393 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00419 (638/152164) while in subpopulation NFE AF= 0.00134 (91/67988). AF 95% confidence interval is 0.00112. There are 18 homozygotes in gnomad4. There are 452 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGG	NM_021870.3	c.*488C>T		3_prime_UTR_variant	Exon 9 of 9	ENST00000336098.8	NP_068656.2
FGG	NM_000509.6	c.1308C>T	p.Asp436Asp	synonymous_variant	Exon 10 of 10		NP_000500.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGG	ENST00000336098	c.*488C>T		3_prime_UTR_variant	Exon 9 of 9	2	NM_021870.3	ENSP00000336829.3

Frequencies

GnomAD3 genomes AF: 0.00420 AC: 638 AN: 152046 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0510

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00728 AC: 935 AN: 128374 Hom.: 30 AF XY: 0.00670 AC XY: 457 AN XY: 68224

Gnomad AFR exome AF: 0.000310

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0535

Gnomad NFE exome AF: 0.000477

Gnomad OTH exome AF: 0.00400

GnomAD4 exome AF: 0.00210 AC: 2850 AN: 1357918 Hom.: 82 Cov.: 27 AF XY: 0.00207 AC XY: 1388 AN XY: 669276

Gnomad4 AFR exome AF: 0.0000349

Gnomad4 AMR exome AF: 0.000113

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000575

Gnomad4 FIN exome AF: 0.0493

Gnomad4 NFE exome AF: 0.000294

Gnomad4 OTH exome AF: 0.00193

GnomAD4 genome AF: 0.00419 AC: 638 AN: 152164 Hom.: 18 Cov.: 33 AF XY: 0.00608 AC XY: 452 AN XY: 74394

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0510

Gnomad4 NFE AF: 0.00134

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00163 Hom.: 2

Bravo AF: 0.000287

Asia WGS AF: 0.000868 AC: 3 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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

Oct 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	4.8
DANN	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs191297318; hg19: chr4-155525498;