rs741810

Positions:

Variant summary

Our verdict is Benign. Variant got -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

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:

FUS (HGNC:):

FUS links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 259594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-31182621-C-A is described in Lovd as [Benign].

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FUS	NM_004960.4 linkuse as main transcript	c.147C>A	p.Gly49Gly	synonymous_variant	3/15	ENST00000254108.12	NP_004951.1	P35637-1Q6IBQ5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FUS	ENST00000254108.12 linkuse as main transcript	c.147C>A	p.Gly49Gly	synonymous_variant	3/15	1	NM_004960.4	ENSP00000254108.8		P35637-1

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

GnomAD3 exomes

AF:

0.324

AC:

81494

AN:

251488

Hom.:

14699

AF XY:

0.335

AC XY:

45509

AN XY:

135922

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 SAS exome

AF:

0.512

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

Gnomad4 AFR exome

AF:

0.0586

Gnomad4 AMR exome

AF:

0.367

Gnomad4 ASJ exome

AF:

0.195

Gnomad4 EAS exome

AF:

0.205

Gnomad4 SAS exome

AF:

0.507

Gnomad4 FIN exome

AF:

0.379

Gnomad4 NFE exome

AF:

0.316

Gnomad4 OTH exome

AF:

0.298

GnomAD4 genome

AF:

0.252

AC:

38397

AN:

152232

Hom.:

6009

Cov.:

AF XY:

0.259

AC XY:

19300

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.0704

Gnomad4 AMR

AF:

0.326

Gnomad4 ASJ

AF:

0.182

Gnomad4 EAS

AF:

0.241

Gnomad4 SAS

AF:

0.524

Gnomad4 FIN

AF:

0.377

Gnomad4 NFE

AF:

0.314

Gnomad4 OTH

AF:

0.234

Alfa

AF:

0.294

Hom.:

7370

Bravo

AF:

0.233

Asia WGS

AF:

0.379

AC:

1314

AN:

3478

EpiCase

AF:

0.299

EpiControl

AF:

0.291

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Amyotrophic lateral sclerosis type 6

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2017	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 13, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Tremor, hereditary essential, 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.89

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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