4-154604393-A-T

Position:

• chr4-154604393-A-T

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.*441T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00471 in 1,461,342 control chromosomes in the GnomAD database, including 297 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (174 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (123 hom.)
• Consequence: FGG NM_021870.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.713

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 (BayesDel_noAF=-0.83).
• BP6: Variant 4-154604393-A-T is Benign according to our data. Variant chr4-154604393-A-T is described in ClinVar as [Benign]. Clinvar id is 1250353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0825 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGG	NM_021870.3	c.*441T>A		3_prime_UTR_variant	9/9	ENST00000336098.8	NP_068656.2
FGG	NM_000509.6	c.1300-39T>A		intron_variant			NP_000500.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGG	ENST00000336098.8	c.*441T>A		3_prime_UTR_variant	9/9	2	NM_021870.3	ENSP00000336829

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3766 AN: 152176 Hom.: 174 Cov.: 32

Gnomad AFR AF: 0.0851

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000558

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.00503 AC: 550 AN: 109432 Hom.: 26 AF XY: 0.00359 AC XY: 211 AN XY: 58760

Gnomad AFR exome AF: 0.0828

Gnomad AMR exome AF: 0.00547

Gnomad ASJ exome AF: 0.00180

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000684

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000423

Gnomad OTH exome AF: 0.00528

GnomAD4 exome AF: 0.00238 AC: 3115 AN: 1309048 Hom.: 123 Cov.: 23 AF XY: 0.00210 AC XY: 1358 AN XY: 646850

Gnomad4 AFR exome AF: 0.0852

Gnomad4 AMR exome AF: 0.00608

Gnomad4 ASJ exome AF: 0.00173

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000751

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000340

Gnomad4 OTH exome AF: 0.00563

GnomAD4 genome AF: 0.0247 AC: 3768 AN: 152294 Hom.: 174 Cov.: 32 AF XY: 0.0233 AC XY: 1738 AN XY: 74470

Gnomad4 AFR AF: 0.0849

Gnomad4 AMR AF: 0.00981

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.00365 Hom.: 4

Bravo AF: 0.0280

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.9
DANN	Benign	0.53

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: rs2066880; hg19: chr4-155525545;