NM_004960.4:c.190+9T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004960.4(FUS):c.190+9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,614,078 control chromosomes in the GnomAD database, including 1,475 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.056 ( 787 hom., cov: 32)

Exomes 𝑓: 0.0079 ( 688 hom. )

Consequence

FUS
NM_004960.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.06

Publications

5 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: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 16-31182673-T-C is Benign according to our data. Variant chr16-31182673-T-C is described in ClinVar as Benign. ClinVar VariationId is 259596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 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	Effect	Exon Rank	Protein	UniProt
FUS	NM_004960.4	MANE Select	c.190+9T>C	intron	N/A	NP_004951.1	P35637-1
FUS	NM_001170634.1		c.190+9T>C	intron	N/A	NP_001164105.1	P35637-2
FUS	NM_001170937.1		c.190+9T>C	intron	N/A	NP_001164408.1	Q13344

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FUS	ENST00000254108.12	TSL:1 MANE Select	c.190+9T>C	intron	N/A	ENSP00000254108.8	P35637-1
FUS	ENST00000380244.8	TSL:1	c.190+9T>C	intron	N/A	ENSP00000369594.3	P35637-2
FUS	ENST00000566605.5	TSL:1	n.190+9T>C	intron	N/A	ENSP00000455073.1	H3BNZ4

Frequencies

GnomAD3 genomes

AF:

0.0559

AC:

8508

AN:

152166

Hom.:

769

Cov.:

show subpopulations

Gnomad AFR

AF:

0.188

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0244

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00972

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00313

Gnomad OTH

AF:

0.0393

GnomAD2 exomes

AF:

0.0166

AC:

4182

AN:

251468

AF XY:

0.0133

show subpopulations

Gnomad AFR exome

AF:

0.191

Gnomad AMR exome

AF:

0.0112

Gnomad ASJ exome

AF:

0.00238

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00296

Gnomad OTH exome

AF:

0.0113

GnomAD4 exome

AF:

0.00785

AC:

11480

AN:

1461794

Hom.:

688

Cov.:

AF XY:

0.00737

AC XY:

5362

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.193

AC:

6449

AN:

33460

American (AMR)

AF:

0.0123

AC:

551

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.00841

AC:

725

AN:

86248

European-Finnish (FIN)

AF:

0.000356

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.0228

AC:

131

AN:

5754

European-Non Finnish (NFE)

AF:

0.00229

AC:

2545

AN:

1111964

Other (OTH)

AF:

0.0165

AC:

997

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

507

1014

1522

2029

2536

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

264

528

792

1056

1320

<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:

0.0563

AC:

8580

AN:

152284

Hom.:

787

Cov.:

AF XY:

0.0538

AC XY:

4005

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.189

AC:

7837

AN:

41518

American (AMR)

AF:

0.0244

AC:

373

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00973

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00313

AC:

213

AN:

68032

Other (OTH)

AF:

0.0417

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

362

724

1086

1448

1810

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

252

336

420

<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:

0.0264

Hom.:

257

Bravo

AF:

0.0626

Asia WGS

AF:

0.0270

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Amyotrophic lateral sclerosis type 6 (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

1.6

(source)

DANN

Benign

0.35

PhyloP100

-1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

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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

Computational scores

Splicing

Publications

Other links and lift over