chr16-31185081-T-TGGCGGC

Variant names:

• chr16-31185081-T-TGGCGGC
• rs72550890
• NM_004960.4:c.681_686dupCGGCGG

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3 BP6

The NM_004960.4(FUS):​c.681_686dupCGGCGG​(p.Gly228_Gly229dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000672 in 1,607,566 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G229G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: FUS NM_004960.4 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.17
• 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 -2 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004960.4
• BP6: Variant 16-31185081-T-TGGCGGC is Benign according to our data. Variant chr16-31185081-T-TGGCGGC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 649131.

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_686dupCGGCGG	p.Gly228_Gly229dup	disruptive_inframe_insertion	Exon 6 of 15	NP_004951.1
	FUS	NM_001170634.1		c.678_683dupCGGCGG	p.Gly227_Gly228dup	disruptive_inframe_insertion	Exon 6 of 15	NP_001164105.1
	FUS	NM_001170937.1		c.669_674dupCGGCGG	p.Gly224_Gly225dup	disruptive_inframe_insertion	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_686dupCGGCGG	p.Gly228_Gly229dup	disruptive_inframe_insertion	Exon 6 of 15	ENSP00000254108.8
	FUS	ENST00000380244.8	TSL:1	c.678_683dupCGGCGG	p.Gly227_Gly228dup	disruptive_inframe_insertion	Exon 6 of 15	ENSP00000369594.3
	FUS	ENST00000566605.5	TSL:1	n.681_686dupCGGCGG		non_coding_transcript_exon	Exon 6 of 14	ENSP00000455073.1

Frequencies

GnomAD3 genomes AF: 0.000119 AC: 18 AN: 151526 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000395

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.0000950

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000737

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000558 AC: 13 AN: 232882 AF XY: 0.0000474

Gnomad AFR exome AF: 0.000135

Gnomad AMR exome AF: 0.0000928

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000195

Gnomad OTH exome AF: 0.000172

GnomAD4 exome AF: 0.0000618 AC: 90 AN: 1455922 Hom.: 0 Cov.: 32 AF XY: 0.0000511 AC XY: 37 AN XY: 723972

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

American (AMR) AF: 0.000254 AC: 11 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: 0.000128 AC: 11 AN: 85976

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52562

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5758

European-Non Finnish (NFE) AF: 0.0000514 AC: 57 AN: 1109310

Other (OTH) AF: 0.0000832 AC: 5 AN: 60112

GnomAD4 genome AF: 0.000119 AC: 18 AN: 151644 Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12 AN XY: 74094

African (AFR) AF: 0.000121 AC: 5 AN: 41326

American (AMR) AF: 0.000394 AC: 6 AN: 15218

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4784

European-Finnish (FIN) AF: 0.0000950 AC: 1 AN: 10522

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

European-Non Finnish (NFE) AF: 0.0000737 AC: 5 AN: 67876

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.0000364 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=81/19	polymorphism

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;