16-31183958-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004960.4(FUS):c.291C>T(p.Tyr97Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 1,613,822 control chromosomes in the GnomAD database, including 224,732 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.46 ( 17825 hom., cov: 31)

Exomes 𝑓: 0.53 ( 206907 hom. )

Consequence

FUS
NM_004960.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.471

Publications

58 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 16-31183958-C-T is Benign according to our data. Variant chr16-31183958-C-T is described in ClinVar as Benign. ClinVar VariationId is 259598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.471 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.734 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FUS	NM_004960.4 link	c.291C>T	p.Tyr97Tyr	synonymous_variant	Exon 4 of 15	ENST00000254108.12	NP_004951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FUS	ENST00000254108.12 link	c.291C>T	p.Tyr97Tyr	synonymous_variant	Exon 4 of 15	1	NM_004960.4	ENSP00000254108.8

Frequencies

GnomAD3 genomes

AF:

0.463

AC:

70374

AN:

151882

Hom.:

17826

Cov.:

show subpopulations

Gnomad AFR

AF:

0.260

Gnomad AMI

AF:

0.696

Gnomad AMR

AF:

0.522

Gnomad ASJ

AF:

0.711

Gnomad EAS

AF:

0.753

Gnomad SAS

AF:

0.439

Gnomad FIN

AF:

0.486

Gnomad MID

AF:

0.703

Gnomad NFE

AF:

0.530

Gnomad OTH

AF:

0.552

GnomAD2 exomes

AF:

0.528

AC:

132857

AN:

251440

AF XY:

0.530

show subpopulations

Gnomad AFR exome

AF:

0.255

Gnomad AMR exome

AF:

0.536

Gnomad ASJ exome

AF:

0.699

Gnomad EAS exome

AF:

0.747

Gnomad FIN exome

AF:

0.490

Gnomad NFE exome

AF:

0.544

Gnomad OTH exome

AF:

0.550

GnomAD4 exome

AF:

0.527

AC:

769753

AN:

1461822

Hom.:

206907

Cov.:

AF XY:

0.526

AC XY:

382773

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.253

AC:

8459

AN:

33478

American (AMR)

AF:

0.540

AC:

24170

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.700

AC:

18295

AN:

26132

East Asian (EAS)

AF:

0.793

AC:

31501

AN:

39700

South Asian (SAS)

AF:

0.447

AC:

38534

AN:

86256

European-Finnish (FIN)

AF:

0.488

AC:

26046

AN:

53414

Middle Eastern (MID)

AF:

0.717

AC:

4133

AN:

5768

European-Non Finnish (NFE)

AF:

0.527

AC:

586175

AN:

1111958

Other (OTH)

AF:

0.537

AC:

32440

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

22449

44898

67347

89796

112245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16704

33408

50112

66816

83520

<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:

0.463

AC:

70377

AN:

152000

Hom.:

17825

Cov.:

AF XY:

0.463

AC XY:

34394

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.260

AC:

10766

AN:

41480

American (AMR)

AF:

0.522

AC:

7975

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.711

AC:

2468

AN:

3470

East Asian (EAS)

AF:

0.754

AC:

3893

AN:

5166

South Asian (SAS)

AF:

0.439

AC:

2117

AN:

4822

European-Finnish (FIN)

AF:

0.486

AC:

5113

AN:

10520

Middle Eastern (MID)

AF:

0.711

AC:

209

AN:

294

European-Non Finnish (NFE)

AF:

0.530

AC:

36043

AN:

67956

Other (OTH)

AF:

0.548

AC:

1158

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1799

3598

5397

7196

8995

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

638

1276

1914

2552

3190

<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:

0.528

Hom.:

42899

Bravo

AF:

0.466

Asia WGS

AF:

0.521

AC:

1815

AN:

3478

EpiCase

AF:

0.558

EpiControl

AF:

0.572

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Amyotrophic lateral sclerosis type 6

Benign:2

May 31, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 13, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Tremor, hereditary essential, 4

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 04, 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

BayesDel_noAF

Benign

-0.49

CADD

Benign

6.0

(source)

DANN

Benign

0.88

PhyloP100

0.47

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over