Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_004960.4(FUS):c.147C>A(p.Gly49Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 1,613,822 control chromosomes in the GnomAD database, including 84,595 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 6009 hom., cov: 33)

Exomes 𝑓: 0.32 ( 78586 hom. )

Consequence

FUS
NM_004960.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.473

Publications

52 publications found

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 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)

FUS links:

ENSG00000260304 (HGNC:):

ENSG00000260304 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.32).

BP6

Variant 16-31182621-C-A is Benign according to our data. Variant chr16-31182621-C-A is described in ClinVar as Benign. ClinVar VariationId is 259594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.473 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.507 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FUS	NM_004960.4	MANE Select	c.147C>A	p.Gly49Gly	synonymous	Exon 3 of 15	NP_004951.1
FUS	NM_001170634.1		c.147C>A	p.Gly49Gly	synonymous	Exon 3 of 15	NP_001164105.1
FUS	NM_001170937.1		c.147C>A	p.Gly49Gly	synonymous	Exon 3 of 15	NP_001164408.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FUS	ENST00000254108.12	TSL:1 MANE Select	c.147C>A	p.Gly49Gly	synonymous	Exon 3 of 15	ENSP00000254108.8
FUS	ENST00000380244.8	TSL:1	c.147C>A	p.Gly49Gly	synonymous	Exon 3 of 15	ENSP00000369594.3
FUS	ENST00000566605.5	TSL:1	n.147C>A		non_coding_transcript_exon	Exon 3 of 14	ENSP00000455073.1

Frequencies

GnomAD3 genomes

AF:

0.252

AC:

38390

AN:

152114

Hom.:

6007

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0706

Gnomad AMI

AF:

0.212

Gnomad AMR

AF:

0.326

Gnomad ASJ

AF:

0.182

Gnomad EAS

AF:

0.242

Gnomad SAS

AF:

0.525

Gnomad FIN

AF:

0.377

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.314

Gnomad OTH

AF:

0.230

GnomAD2 exomes

AF:

0.324

AC:

81494

AN:

251488

AF XY:

0.335

show subpopulations

Gnomad AFR exome

AF:

0.0634

Gnomad AMR exome

AF:

0.378

Gnomad ASJ exome

AF:

0.196

Gnomad EAS exome

AF:

0.249

Gnomad FIN exome

AF:

0.376

Gnomad NFE exome

AF:

0.308

Gnomad OTH exome

AF:

0.319

GnomAD4 exome

AF:

0.319

AC:

466135

AN:

1461590

Hom.:

78586

Cov.:

AF XY:

0.323

AC XY:

235159

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.0586

AC:

1963

AN:

33480

American (AMR)

AF:

0.367

AC:

16399

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.195

AC:

5094

AN:

26136

East Asian (EAS)

AF:

0.205

AC:

8119

AN:

39700

South Asian (SAS)

AF:

0.507

AC:

43772

AN:

86254

European-Finnish (FIN)

AF:

0.379

AC:

20229

AN:

53416

Middle Eastern (MID)

AF:

0.192

AC:

1103

AN:

5754

European-Non Finnish (NFE)

AF:

0.316

AC:

351459

AN:

1111740

Other (OTH)

AF:

0.298

AC:

17997

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

17807

35614

53422

71229

89036

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11540

23080

34620

46160

57700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.252

AC:

38397

AN:

152232

Hom.:

6009

Cov.:

AF XY:

0.259

AC XY:

19300

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.0704

AC:

2928

AN:

41568

American (AMR)

AF:

0.326

AC:

4983

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.182

AC:

631

AN:

3466

East Asian (EAS)

AF:

0.241

AC:

1247

AN:

5172

South Asian (SAS)

AF:

0.524

AC:

2533

AN:

4830

European-Finnish (FIN)

AF:

0.377

AC:

3996

AN:

10592

Middle Eastern (MID)

AF:

0.160

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.314

AC:

21345

AN:

67998

Other (OTH)

AF:

0.234

AC:

494

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1404

2808

4212

5616

7020

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

408

816

1224

1632

2040

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.289

Hom.:

8912

Bravo

AF:

0.233

Asia WGS

AF:

0.379

AC:

1314

AN:

3478

EpiCase

AF:

0.299

EpiControl

AF:

0.291

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Amyotrophic lateral sclerosis type 6 (2)

not provided (2)

Amyotrophic lateral sclerosis type 6;C3539195:Tremor, hereditary essential, 4 (1)

Tremor, hereditary essential, 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

0.47

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs741810

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over