chr16-31182526-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM5BP4_StrongBP6_Moderate

The NM_004960.4(FUS):​c.52C>A​(p.Pro18Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,614,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P18S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

FUS
NM_004960.4 missense

Scores

4
15

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.12
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chr16-31182526-C-T is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.026498377).
BP6
Variant 16-31182526-C-A is Benign according to our data. Variant chr16-31182526-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1113414.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-31182526-C-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FUSNM_004960.4 linkuse as main transcriptc.52C>A p.Pro18Thr missense_variant 3/15 ENST00000254108.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FUSENST00000254108.12 linkuse as main transcriptc.52C>A p.Pro18Thr missense_variant 3/151 NM_004960.4 P4P35637-1
ENST00000564743.1 linkuse as main transcriptn.448G>T non_coding_transcript_exon_variant 2/25

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152126
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000771
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000127
AC:
32
AN:
251442
Hom.:
0
AF XY:
0.000110
AC XY:
15
AN XY:
135912
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00174
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000212
AC:
31
AN:
1461870
Hom.:
0
Cov.:
31
AF XY:
0.0000220
AC XY:
16
AN XY:
727228
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000655
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152244
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74444
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000773
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Bravo
AF:
0.0000302
ExAC
AF:
0.000115
AC:
14
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 6;C3539195:Tremor, hereditary essential, 4 Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeSep 08, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Uncertain
-0.010
CADD
Uncertain
23
DANN
Benign
0.92
DEOGEN2
Benign
0.27
T;.;T
Eigen
Benign
-0.31
Eigen_PC
Benign
-0.10
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.71
T;T;T
M_CAP
Benign
0.035
D
MetaRNN
Benign
0.026
T;T;T
MetaSVM
Benign
-0.65
T
MutationAssessor
Benign
0.85
L;L;.
MutationTaster
Benign
0.94
D;D;D
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-0.33
N;N;N
REVEL
Uncertain
0.38
Sift
Benign
0.27
T;T;T
Sift4G
Benign
0.51
T;T;T
Polyphen
0.018
B;B;.
Vest4
0.50
MVP
0.95
MPC
0.22
ClinPred
0.057
T
GERP RS
4.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.089
gMVP
0.39

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.

Other links and lift over

dbSNP: rs144888138; hg19: chr16-31193847; COSMIC: COSV99568682; COSMIC: COSV99568682; API