16-31192208-G-C

Position:

• chr16-31192208-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001170634.1(FUS):​c.*770G>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 0.309 in 526,328 control chromosomes in the GnomAD database, including 28,666 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.26 (6043 hom., cov: 31)
  • Exomes 𝑓: 0.33 (22623 hom.)
• Consequence: FUS NM_001170634.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0150

Genes affected

FUS (HGNC:4010): (FUS RNA binding protein) This gene encodes a multifunctional protein component of the heterogeneous nuclear ribonucleoprotein (hnRNP) complex. The hnRNP complex is involved in pre-mRNA splicing and the export of fully processed mRNA to the cytoplasm. This protein belongs to the FET family of RNA-binding proteins which have been implicated in cellular processes that include regulation of gene expression, maintenance of genomic integrity and mRNA/microRNA processing. Alternative splicing results in multiple transcript variants. Defects in this gene result in amyotrophic lateral sclerosis type 6. [provided by RefSeq, Sep 2009]

FUS (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 16-31192208-G-C is Benign according to our data. Variant chr16-31192208-G-C is described in ClinVar as [Benign]. Clinvar id is 319004.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FUS	NM_001170634.1	c.*770G>C		3_prime_UTR_variant	15/15		NP_001164105.1
FUS	NM_001170937.1	c.*770G>C		3_prime_UTR_variant	15/15		NP_001164408.1
FUS	XM_011545781.2	c.*770G>C		3_prime_UTR_variant	15/15		XP_011544083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38803 AN: 151904 Hom.: 6041 Cov.: 31

Gnomad AFR AF: 0.0788

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.241

Gnomad SAS AF: 0.530

Gnomad FIN AF: 0.377

Gnomad MID AF: 0.172

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.234

GnomAD3 exomes AF: 0.336 AC: 43057 AN: 128058 Hom.: 8035 AF XY: 0.348 AC XY: 24409 AN XY: 70124

Gnomad AFR exome AF: 0.0673

Gnomad AMR exome AF: 0.374

Gnomad ASJ exome AF: 0.197

Gnomad EAS exome AF: 0.251

Gnomad SAS exome AF: 0.509

Gnomad FIN exome AF: 0.388

Gnomad NFE exome AF: 0.309

Gnomad OTH exome AF: 0.313

GnomAD4 exome AF: 0.330 AC: 123567 AN: 374306 Hom.: 22623 Cov.: 0 AF XY: 0.345 AC XY: 70785 AN XY: 205448

Gnomad4 AFR exome AF: 0.0713

Gnomad4 AMR exome AF: 0.369

Gnomad4 ASJ exome AF: 0.198

Gnomad4 EAS exome AF: 0.207

Gnomad4 SAS exome AF: 0.507

Gnomad4 FIN exome AF: 0.382

Gnomad4 NFE exome AF: 0.310

Gnomad4 OTH exome AF: 0.293

GnomAD4 genome AF: 0.255 AC: 38812 AN: 152022 Hom.: 6043 Cov.: 31 AF XY: 0.263 AC XY: 19516 AN XY: 74306

Gnomad4 AFR AF: 0.0786

Gnomad4 AMR AF: 0.329

Gnomad4 ASJ AF: 0.187

Gnomad4 EAS AF: 0.240

Gnomad4 SAS AF: 0.530

Gnomad4 FIN AF: 0.377

Gnomad4 NFE AF: 0.314

Gnomad4 OTH AF: 0.238

Alfa AF: 0.211 Hom.: 785

Bravo AF: 0.236

Asia WGS AF: 0.380 AC: 1320 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Amyotrophic lateral sclerosis type 6 Benign:1

Benign, 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 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
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.4
DANN	Benign	0.78

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: rs4889537; hg19: chr16-31203529;