rs73530283

Positions:

• chr16-31182673-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004960.4(FUS):​c.190+9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,614,078 control chromosomes in the GnomAD database, including 1,475 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (787 hom., cov: 32)
  • Exomes 𝑓: 0.0079 (688 hom.)
• Consequence: FUS NM_004960.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.06

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-31182673-T-C is Benign according to our data. Variant chr16-31182673-T-C is described in ClinVar as [Benign]. Clinvar id is 259596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-31182673-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FUS	NM_004960.4	c.190+9T>C		intron_variant		ENST00000254108.12	NP_004951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FUS	ENST00000254108.12	c.190+9T>C		intron_variant		1	NM_004960.4	ENSP00000254108	P4
	ENST00000564743.1	n.301A>G		non_coding_transcript_exon_variant	2/2	5

Frequencies

GnomAD3 genomes AF: 0.0559 AC: 8508 AN: 152166 Hom.: 769 Cov.: 32

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0244

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00972

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00313

Gnomad OTH AF: 0.0393

GnomAD3 exomes AF: 0.0166 AC: 4182 AN: 251468 Hom.: 305 AF XY: 0.0133 AC XY: 1809 AN XY: 135906

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.0112

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00826

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00296

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.00785 AC: 11480 AN: 1461794 Hom.: 688 Cov.: 32 AF XY: 0.00737 AC XY: 5362 AN XY: 727196

Gnomad4 AFR exome AF: 0.193

Gnomad4 AMR exome AF: 0.0123

Gnomad4 ASJ exome AF: 0.00230

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00841

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.00229

Gnomad4 OTH exome AF: 0.0165

GnomAD4 genome AF: 0.0563 AC: 8580 AN: 152284 Hom.: 787 Cov.: 32 AF XY: 0.0538 AC XY: 4005 AN XY: 74480

Gnomad4 AFR AF: 0.189

Gnomad4 AMR AF: 0.0244

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00973

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00313

Gnomad4 OTH AF: 0.0417

Alfa AF: 0.0228 Hom.: 173

Bravo AF: 0.0626

Asia WGS AF: 0.0270 AC: 93 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 10, 2019	- -

Amyotrophic lateral sclerosis type 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Amyotrophic lateral sclerosis type 6;C3539195:Tremor, hereditary essential, 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.6
DANN	Benign	0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs73530283; hg19: chr16-31193994;