16-31180161-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004960.4(FUS):c.-54A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.991 in 1,599,102 control chromosomes in the GnomAD database, including 785,741 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.95 ( 69189 hom., cov: 35)

Exomes 𝑓: 0.99 ( 716552 hom. )

Consequence

FUS
NM_004960.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.722

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 16-31180161-A-G is Benign according to our data. Variant chr16-31180161-A-G is described in ClinVar as [Benign]. Clinvar id is 318979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-31180161-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FUS	NM_004960.4 linkuse as main transcript	c.-54A>G		5_prime_UTR_variant	1/15	ENST00000254108.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FUS	ENST00000254108.12 linkuse as main transcript	c.-54A>G		5_prime_UTR_variant	1/15	1	NM_004960.4	P4	P35637-1

Frequencies

GnomAD3 genomes

AF:

0.950

AC:

144592

AN:

152190

Hom.:

69145

Cov.:

show subpopulations

Gnomad AFR

AF:

0.827

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.980

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.994

Gnomad NFE

AF:

0.999

Gnomad OTH

AF:

0.961

GnomAD3 exomes

AF:

0.987

AC:

220268

AN:

223204

Hom.:

108895

AF XY:

0.991

AC XY:

119610

AN XY:

120698

show subpopulations

Gnomad AFR exome

AF:

0.814

Gnomad AMR exome

AF:

0.990

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad SAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

0.999

Gnomad OTH exome

AF:

0.995

GnomAD4 exome

AF:

0.995

AC:

1439425

AN:

1446794

Hom.:

716552

Cov.:

AF XY:

0.996

AC XY:

715182

AN XY:

718302

show subpopulations

Gnomad4 AFR exome

AF:

0.826

Gnomad4 AMR exome

AF:

0.989

Gnomad4 ASJ exome

AF:

1.00

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

1.00

Gnomad4 FIN exome

AF:

1.00

Gnomad4 NFE exome

AF:

1.00

Gnomad4 OTH exome

AF:

0.989

GnomAD4 genome

AF:

0.950

AC:

144695

AN:

152308

Hom.:

69189

Cov.:

AF XY:

0.951

AC XY:

70863

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.827

Gnomad4 AMR

AF:

0.980

Gnomad4 ASJ

AF:

1.00

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

1.00

Gnomad4 FIN

AF:

1.00

Gnomad4 NFE

AF:

0.999

Gnomad4 OTH

AF:

0.961

Alfa

AF:

0.994

Hom.:

85961

Bravo

AF:

0.943

Asia WGS

AF:

0.992

AC:

3451

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 03, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

Cadd

Benign

Dann

Benign

0.63

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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