rs150529460

Positions:

chr16-31191033-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004960.4(FUS):c.1464C>T(p.Gly488=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000484 in 1,611,786 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00081 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00045 ( 3 hom. )

Consequence

FUS
NM_004960.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -4.48

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 16-31191033-C-T is Benign according to our data. Variant chr16-31191033-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 259593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-31191033-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-4.48 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000814 (123/151180) while in subpopulation AMR AF= 0.00428 (65/15174). AF 95% confidence interval is 0.00345. There are 1 homozygotes in gnomad4. There are 57 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FUS	NM_004960.4 linkuse as main transcript	c.1464C>T	p.Gly488=	synonymous_variant	14/15	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.1464C>T	p.Gly488=	synonymous_variant	14/15	1	NM_004960.4	ENSP00000254108	P4	P35637-1

Frequencies

GnomAD3 genomes

AF:

0.000814

AC:

123

AN:

151054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000560

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00429

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00332

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000251

Gnomad OTH

AF:

0.000483

GnomAD3 exomes

AF:

0.00105

AC:

262

AN:

249364

Hom.:

AF XY:

0.000849

AC XY:

115

AN XY:

135430

show subpopulations

Gnomad AFR exome

AF:

0.000845

Gnomad AMR exome

AF:

0.00538

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00196

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.000450

AC:

657

AN:

1460606

Hom.:

Cov.:

AF XY:

0.000434

AC XY:

315

AN XY:

726626

show subpopulations

Gnomad4 AFR exome

AF:

0.000598

Gnomad4 AMR exome

AF:

0.00671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00401

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000999

Gnomad4 OTH exome

AF:

0.000796

GnomAD4 genome

AF:

0.000814

AC:

123

AN:

151180

Hom.:

Cov.:

AF XY:

0.000772

AC XY:

AN XY:

73862

show subpopulations

Gnomad4 AFR

AF:

0.000558

Gnomad4 AMR

AF:

0.00428

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00333

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000251

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000345

Hom.:

Bravo

AF:

0.00101

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 24, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Amyotrophic lateral sclerosis type 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

7.1

DANN

Benign

0.62

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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