ENST00000566605.5:n.-49G>T

Variant names:

• chr16-31180089-G-T
• NM_004960.4:c.-126G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000566605.5(FUS):​n.-126G>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FUS ENST00000566605.5 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.226
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• amyotrophic lateral sclerosis type 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• juvenile amyotrophic lateral sclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• tremor, hereditary essential, 4

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FUS	NM_004960.4	c.-126G>T		upstream_gene_variant		ENST00000254108.12	NP_004951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FUS	ENST00000254108.12	c.-126G>T		upstream_gene_variant		1	NM_004960.4	ENSP00000254108.8

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1247296 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 621632

African (AFR) AF: 0.00 AC: 0 AN: 28528

American (AMR) AF: 0.00 AC: 0 AN: 35550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24168

East Asian (EAS) AF: 0.00 AC: 0 AN: 35076

South Asian (SAS) AF: 0.00 AC: 0 AN: 76256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5386

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 940604

Other (OTH) AF: 0.00 AC: 0 AN: 53106

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.0
DANN	Benign	0.81
PhyloP100		-0.23
PromoterAI		-0.017	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr16-31191410;