dbSNP rs80301724: FUS:c.*41G>A (chr16-31191479-G-A) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_004960.4(FUS):c.*41G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00711 in 1,604,660 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 3 hom., cov: 31)

Exomes 𝑓: 0.0073 ( 63 hom. )

Consequence

FUS
NM_004960.4 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.45

Publications

12 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.28).

BP6

Variant 16-31191479-G-A is Benign according to our data. Variant chr16-31191479-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 318993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00567 (854/150710) while in subpopulation AMR AF = 0.00996 (150/15064). AF 95% confidence interval is 0.00866. There are 3 homozygotes in GnomAd4. There are 385 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR,Unknown gene

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
FUS	NM_004960.4	MANE Select	c.*41G>A	3_prime_UTR	Exon 15 of 15	NP_004951.1
FUS	NM_001170634.1		c.*41G>A	3_prime_UTR	Exon 15 of 15	NP_001164105.1
FUS	NM_001170937.1		c.*41G>A	3_prime_UTR	Exon 15 of 15	NP_001164408.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
FUS	ENST00000254108.12	TSL:1 MANE Select	c.*41G>A	3_prime_UTR	Exon 15 of 15	ENSP00000254108.8
FUS	ENST00000380244.8	TSL:1	c.*41G>A	3_prime_UTR	Exon 15 of 15	ENSP00000369594.3
FUS	ENST00000566605.5	TSL:1	n.*795G>A	non_coding_transcript_exon	Exon 14 of 14	ENSP00000455073.1

Frequencies

GnomAD3 genomes

AF:

0.00565

AC:

851

AN:

150598

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00997

Gnomad ASJ

AF:

0.0136

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00709

Gnomad FIN

AF:

0.000782

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00789

Gnomad OTH

AF:

0.00967

GnomAD2 exomes

AF:

0.00669

AC:

1681

AN:

251238

AF XY:

0.00729

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00674

Gnomad ASJ exome

AF:

0.0146

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00116

Gnomad NFE exome

AF:

0.00798

Gnomad OTH exome

AF:

0.00766

GnomAD4 exome

AF:

0.00726

AC:

10557

AN:

1453950

Hom.:

Cov.:

AF XY:

0.00745

AC XY:

5395

AN XY:

723866

show subpopulations

African (AFR)

AF:

0.00114

AC:

AN:

33322

American (AMR)

AF:

0.00689

AC:

308

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0125

AC:

326

AN:

26080

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39654

South Asian (SAS)

AF:

0.0102

AC:

879

AN:

86092

European-Finnish (FIN)

AF:

0.000936

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.0255

AC:

145

AN:

5678

European-Non Finnish (NFE)

AF:

0.00747

AC:

8257

AN:

1104916

Other (OTH)

AF:

0.00920

AC:

553

AN:

60102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

625

1250

1876

2501

3126

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

304

608

912

1216

1520

<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:

0.00567

AC:

854

AN:

150710

Hom.:

Cov.:

AF XY:

0.00524

AC XY:

385

AN XY:

73472

show subpopulations

African (AFR)

AF:

0.00125

AC:

AN:

40900

American (AMR)

AF:

0.00996

AC:

150

AN:

15064

Ashkenazi Jewish (ASJ)

AF:

0.0136

AC:

AN:

3466

East Asian (EAS)

AF:

0.000195

AC:

AN:

5140

South Asian (SAS)

AF:

0.00751

AC:

AN:

4792

European-Finnish (FIN)

AF:

0.000782

AC:

AN:

10224

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00790

AC:

536

AN:

67830

Other (OTH)

AF:

0.00958

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

127

169

211

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00745

Hom.:

Bravo

AF:

0.00604

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Amyotrophic lateral sclerosis type 6 (2)

not provided (2)

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

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.80

PhyloP100

1.4

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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.

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