16-31182673-T-C

Position:

chr16-31182673-T-C

Variant summary

Our verdict is Benign. Variant got -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

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:

(HGNC:):

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=-0.87).

BP6

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

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 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.190+9T>C		intron_variant		ENST00000254108.12	NP_004951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FUS	ENST00000254108.12 linkuse as main transcript	c.190+9T>C		intron_variant		1	NM_004960.4	ENSP00000254108	P4	P35637-1
	ENST00000564743.1 linkuse as main transcript	n.301A>G		non_coding_transcript_exon_variant	2/2	5

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

GnomAD3 exomes

AF:

0.0166

AC:

4182

AN:

251468

Hom.:

305

AF XY:

0.0133

AC XY:

1809

AN XY:

135906

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 SAS exome

AF:

0.00826

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

Gnomad4 AFR exome

AF:

0.193

Gnomad4 AMR exome

AF:

0.0123

Gnomad4 ASJ exome

AF:

0.00230

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00841

Gnomad4 FIN exome

AF:

0.000356

Gnomad4 NFE exome

AF:

0.00229

Gnomad4 OTH exome

AF:

0.0165

GnomAD4 genome

AF:

0.0563

AC:

8580

AN:

152284

Hom.:

787

Cov.:

AF XY:

0.0538

AC XY:

4005

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.189

Gnomad4 AMR

AF:

0.0244

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00973

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00313

Gnomad4 OTH

AF:

0.0417

Alfa

AF:

0.0228

Hom.:

173

Bravo

AF:

0.0626

Asia WGS

AF:

0.0270

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 10, 2019	- -

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. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

1.6

DANN

Benign

0.35

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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