chr16-31185093-CGGCGGCGGT-C

Variant names:

• chr16-31185093-CGGCGGCGGT-C
• rs767564995
• NM_004960.4:c.681_689delCGGCGGTGG

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS1

The NM_004960.4(FUS):​c.681_689delCGGCGGTGG​(p.Gly228_Gly230del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000156 in 1,605,334 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G227G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: FUS NM_004960.4 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.91
• Publications: 1 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: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• juvenile amyotrophic lateral sclerosis

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

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004960.4
• BP6: Variant 16-31185093-CGGCGGCGGT-C is Benign according to our data. Variant chr16-31185093-CGGCGGCGGT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 447358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00016 (233/1453558) while in subpopulation MID AF = 0.00087 (5/5750). AF 95% confidence interval is 0.000351. There are 1 homozygotes in GnomAdExome4. There are 133 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.

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.681_689delCGGCGGTGG	p.Gly228_Gly230del	disruptive_inframe_deletion	Exon 6 of 15	NP_004951.1
	FUS	NM_001170634.1		c.678_686delCGGCGGTGG	p.Gly227_Gly229del	disruptive_inframe_deletion	Exon 6 of 15	NP_001164105.1
	FUS	NM_001170937.1		c.669_677delCGGCGGTGG	p.Gly224_Gly226del	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.681_689delCGGCGGTGG	p.Gly228_Gly230del	disruptive_inframe_deletion	Exon 6 of 15	ENSP00000254108.8
	FUS	ENST00000380244.8	TSL:1	c.678_686delCGGCGGTGG	p.Gly227_Gly229del	disruptive_inframe_deletion	Exon 6 of 15	ENSP00000369594.3
	FUS	ENST00000566605.5	TSL:1	n.681_689delCGGCGGTGG		non_coding_transcript_exon	Exon 6 of 14	ENSP00000455073.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 151658 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000628

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000178 AC: 41 AN: 230104 AF XY: 0.000231

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.000175

GnomAD4 exome AF: 0.000160 AC: 233 AN: 1453558 Hom.: 1 AF XY: 0.000184 AC XY: 133 AN XY: 722660

African (AFR) AF: 0.0000299 AC: 1 AN: 33400

American (AMR) AF: 0.00 AC: 0 AN: 42726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25976

East Asian (EAS) AF: 0.000279 AC: 11 AN: 39422

South Asian (SAS) AF: 0.000466 AC: 40 AN: 85826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52240

Middle Eastern (MID) AF: 0.000870 AC: 5 AN: 5750

European-Non Finnish (NFE) AF: 0.000154 AC: 171 AN: 1108216

Other (OTH) AF: 0.0000833 AC: 5 AN: 60002

GnomAD4 genome AF: 0.000112 AC: 17 AN: 151776 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74162

African (AFR) AF: 0.00 AC: 0 AN: 41378

American (AMR) AF: 0.0000656 AC: 1 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000628 AC: 3 AN: 4776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000192 AC: 13 AN: 67880

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.0000945

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Amyotrophic lateral sclerosis type 6;C3539195:Tremor, hereditary essential, 4 (1)
-	-	1	FUS-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.9
Mutation Taster		=145/55	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs767564995; hg19: chr16-31196414;