16-31184934-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004960.4(FUS):​c.524-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00252 in 1,609,054 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 41 hom., cov: 32)
Exomes 𝑓: 0.0014 ( 48 hom. )

Consequence

FUS
NM_004960.4 splice_region, intron

Scores

2
Splicing: ADA: 0.00005232
2

Clinical Significance

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

Conservation

PhyloP100: 0.0820
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.78).
BP6
Variant 16-31184934-C-T is Benign according to our data. Variant chr16-31184934-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 318985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-31184934-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0138 (2080/151100) while in subpopulation AFR AF= 0.0481 (1975/41086). AF 95% confidence interval is 0.0463. There are 41 homozygotes in gnomad4. There are 974 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 41 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FUSNM_004960.4 linkc.524-5C>T splice_region_variant, intron_variant Intron 5 of 14 ENST00000254108.12 NP_004951.1 P35637-1Q6IBQ5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FUSENST00000254108.12 linkc.524-5C>T splice_region_variant, intron_variant Intron 5 of 14 1 NM_004960.4 ENSP00000254108.8 P35637-1

Frequencies

GnomAD3 genomes
AF:
0.0138
AC:
2080
AN:
150984
Hom.:
41
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00496
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.0101
GnomAD3 exomes
AF:
0.00366
AC:
910
AN:
248322
Hom.:
19
AF XY:
0.00270
AC XY:
363
AN XY:
134454
show subpopulations
Gnomad AFR exome
AF:
0.0486
Gnomad AMR exome
AF:
0.00266
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000135
Gnomad OTH exome
AF:
0.00230
GnomAD4 exome
AF:
0.00136
AC:
1979
AN:
1457954
Hom.:
48
Cov.:
32
AF XY:
0.00116
AC XY:
840
AN XY:
725574
show subpopulations
Gnomad4 AFR exome
AF:
0.0491
Gnomad4 AMR exome
AF:
0.00274
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000581
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000280
Gnomad4 OTH exome
AF:
0.00294
GnomAD4 genome
AF:
0.0138
AC:
2080
AN:
151100
Hom.:
41
Cov.:
32
AF XY:
0.0132
AC XY:
974
AN XY:
73716
show subpopulations
Gnomad4 AFR
AF:
0.0481
Gnomad4 AMR
AF:
0.00495
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.0100
Alfa
AF:
0.00507
Hom.:
12
Bravo
AF:
0.0157
Asia WGS
AF:
0.00289
AC:
11
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000237

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Dec 27, 2017
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Oct 06, 2020
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

FUS-related disorder Benign:1
Jan 24, 2024
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Amyotrophic lateral sclerosis type 6 Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Dec 28, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.78
CADD
Benign
0.88
DANN
Benign
0.57
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000052
dbscSNV1_RF
Benign
0.0
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.

Other links and lift over

dbSNP: rs73530287; hg19: chr16-31196255; API