16-31185081-TGGCGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGC

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_004960.4(FUS):c.684_686dupCGG(p.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 0.00144 in 1,607,566 control chromosomes in the GnomAD database, including 12 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G229G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0047 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 8 hom. )

Consequence

FUS
NM_004960.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.17

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 16-31185081-T-TGGC is Benign according to our data. Variant chr16-31185081-T-TGGC is described in ClinVar as [Likely_benign]. Clinvar id is 318986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00466 (707/151644) while in subpopulation AFR AF= 0.0143 (589/41326). AF 95% confidence interval is 0.0133. There are 4 homozygotes in gnomad4. There are 346 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FUS	NM_004960.4 link	c.684_686dupCGG	p.Gly229dup	disruptive_inframe_insertion	Exon 6 of 15	ENST00000254108.12	NP_004951.1	P35637-1Q6IBQ5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FUS	ENST00000254108.12 link	c.684_686dupCGG	p.Gly229dup	disruptive_inframe_insertion	Exon 6 of 15	1	NM_004960.4	ENSP00000254108.8		P35637-1

Frequencies

GnomAD3 genomes

AF:

0.00464

AC:

703

AN:

151526

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0142

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00250

Gnomad ASJ

AF:

0.00116

Gnomad EAS

AF:

0.00368

Gnomad SAS

AF:

0.00188

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000575

Gnomad OTH

AF:

0.00336

GnomAD3 exomes

AF:

0.00164

AC:

382

AN:

232882

Hom.:

AF XY:

0.00150

AC XY:

190

AN XY:

126646

show subpopulations

Gnomad AFR exome

AF:

0.0102

Gnomad AMR exome

AF:

0.00124

Gnomad ASJ exome

AF:

0.000716

Gnomad EAS exome

AF:

0.00317

Gnomad SAS exome

AF:

0.00187

Gnomad FIN exome

AF:

0.000195

Gnomad NFE exome

AF:

0.000547

Gnomad OTH exome

AF:

0.00241

GnomAD4 exome

AF:

0.00111

AC:

1612

AN:

1455922

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

752

AN XY:

723972

show subpopulations

Gnomad4 AFR exome

AF:

0.0143

Gnomad4 AMR exome

AF:

0.00136

Gnomad4 ASJ exome

AF:

0.000422

Gnomad4 EAS exome

AF:

0.00175

Gnomad4 SAS exome

AF:

0.00204

Gnomad4 FIN exome

AF:

0.000209

Gnomad4 NFE exome

AF:

0.000559

Gnomad4 OTH exome

AF:

0.00309

GnomAD4 genome

AF:

0.00466

AC:

707

AN:

151644

Hom.:

Cov.:

AF XY:

0.00467

AC XY:

346

AN XY:

74094

show subpopulations

Gnomad4 AFR

AF:

0.0143

Gnomad4 AMR

AF:

0.00250

Gnomad4 ASJ

AF:

0.00116

Gnomad4 EAS

AF:

0.00369

Gnomad4 SAS

AF:

0.00188

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000575

Gnomad4 OTH

AF:

0.00380

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FUS: BS1 -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 10, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FUS-related disorder

Benign:1

May 26, 2022

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Amyotrophic Lateral Sclerosis, Dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Amyotrophic lateral sclerosis type 6;C3539195:Tremor, hereditary essential, 4

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over