rs74015090

chr16-31184918-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.524-21T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,594,272 control chromosomes in the GnomAD database, including 1,072 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (555 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (517 hom.)
• Consequence: FUS NM_004960.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.33

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-31184918-T-C is Benign according to our data. Variant chr16-31184918-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 259599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FUS	NM_004960.4	c.524-21T>C		intron_variant		ENST00000254108.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FUS	ENST00000254108.12	c.524-21T>C		intron_variant		1	NM_004960.4	P4

Frequencies

GnomAD3 genomes AF: 0.0477 AC: 7237 AN: 151844 Hom.: 551 Cov.: 32

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0199

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00955

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00303

Gnomad OTH AF: 0.0330

GnomAD3 exomes AF: 0.0148 AC: 3662 AN: 247732 Hom.: 227 AF XY: 0.0118 AC XY: 1585 AN XY: 134168

Gnomad AFR exome AF: 0.165

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.000797

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00815

Gnomad FIN exome AF: 0.000188

Gnomad NFE exome AF: 0.00294

Gnomad OTH exome AF: 0.0102

GnomAD4 exome AF: 0.00706 AC: 10188 AN: 1442312 Hom.: 517 Cov.: 30 AF XY: 0.00674 AC XY: 4844 AN XY: 718480

Gnomad4 AFR exome AF: 0.166

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.000462

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.00837

Gnomad4 FIN exome AF: 0.000358

Gnomad4 NFE exome AF: 0.00227

Gnomad4 OTH exome AF: 0.0141

GnomAD4 genome AF: 0.0479 AC: 7275 AN: 151960 Hom.: 555 Cov.: 32 AF XY: 0.0458 AC XY: 3406 AN XY: 74312

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.0199

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00956

Gnomad4 FIN AF: 0.000284

Gnomad4 NFE AF: 0.00303

Gnomad4 OTH AF: 0.0341

Alfa AF: 0.0377 Hom.: 38

Bravo AF: 0.0536

Asia WGS AF: 0.0180 AC: 62 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.79
Dann	Benign	0.28

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: rs74015090; hg19: chr16-31196239;