16-31185081-TGGCGGCGGCGGCGGC-TGGC

Variant names:

• chr16-31185081-TGGCGGCGGCGGC-T
• rs72550890
• NM_004960.4:c.675_686delCGGCGGCGGCGG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_004960.4(FUS):​c.675_686delCGGCGGCGGCGG​(p.Gly226_Gly229del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000056 in 1,607,448 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G225G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: FUS NM_004960.4 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.05
• Publications: 2 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 -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004960.4

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004960.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FUS	NM_004960.4	MANE Select	c.675_686delCGGCGGCGGCGG	p.Gly226_Gly229del	disruptive_inframe_deletion	Exon 6 of 15	NP_004951.1
	FUS	NM_001170634.1		c.672_683delCGGCGGCGGCGG	p.Gly225_Gly228del	disruptive_inframe_deletion	Exon 6 of 15	NP_001164105.1
	FUS	NM_001170937.1		c.663_674delCGGCGGCGGCGG	p.Gly222_Gly225del	disruptive_inframe_deletion	Exon 6 of 15	NP_001164408.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FUS	ENST00000254108.12	TSL:1 MANE Select	c.675_686delCGGCGGCGGCGG	p.Gly226_Gly229del	disruptive_inframe_deletion	Exon 6 of 15	ENSP00000254108.8
	FUS	ENST00000380244.8	TSL:1	c.672_683delCGGCGGCGGCGG	p.Gly225_Gly228del	disruptive_inframe_deletion	Exon 6 of 15	ENSP00000369594.3
	FUS	ENST00000566605.5	TSL:1	n.675_686delCGGCGGCGGCGG		non_coding_transcript_exon	Exon 6 of 14	ENSP00000455073.1

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151526 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1455922 Hom.: 0 AF XY: 0.00000553 AC XY: 4 AN XY: 723972

African (AFR) AF: 0.0000300 AC: 1 AN: 33388

American (AMR) AF: 0.00 AC: 0 AN: 43236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26042

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39538

South Asian (SAS) AF: 0.00 AC: 0 AN: 85976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1109310

Other (OTH) AF: 0.00 AC: 0 AN: 60112

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151526 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73966

African (AFR) AF: 0.00 AC: 0 AN: 41204

American (AMR) AF: 0.00 AC: 0 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67884

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000364 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Amyotrophic lateral sclerosis type 6;C3539195:Tremor, hereditary essential, 4 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.1
Mutation Taster		=71/129	disease causing

Splicing

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

Other links and lift over

dbSNP: rs72550890; hg19: chr16-31196402;