rs68121698

Variant names:

• chr16-31191235-A-T
• rs68121698
• NM_004960.4:c.1541+125A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004960.4(FUS):​c.1541+125A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00541 in 1,477,556 control chromosomes in the GnomAD database, including 137 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (64 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (73 hom.)
• Consequence: FUS NM_004960.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.321
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• amyotrophic lateral sclerosis type 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• juvenile amyotrophic lateral sclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• tremor, hereditary essential, 4

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 16-31191235-A-T is Benign according to our data. Variant chr16-31191235-A-T is described in ClinVar as Benign. ClinVar VariationId is 1236086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0531 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FUS	NM_004960.4	c.1541+125A>T		intron_variant	Intron 14 of 14	ENST00000254108.12	NP_004951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FUS	ENST00000254108.12	c.1541+125A>T		intron_variant	Intron 14 of 14	1	NM_004960.4	ENSP00000254108.8

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2711 AN: 152138 Hom.: 64 Cov.: 32

Gnomad AFR AF: 0.0548

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00272

Gnomad OTH AF: 0.0182

GnomAD4 exome AF: 0.00398 AC: 5271 AN: 1325300 Hom.: 73 Cov.: 20 AF XY: 0.00402 AC XY: 2665 AN XY: 662780

African (AFR) AF: 0.0558 AC: 1692 AN: 30308

American (AMR) AF: 0.00637 AC: 247 AN: 38794

Ashkenazi Jewish (ASJ) AF: 0.0000805 AC: 2 AN: 24840

East Asian (EAS) AF: 0.0000527 AC: 2 AN: 37960

South Asian (SAS) AF: 0.00795 AC: 648 AN: 81492

European-Finnish (FIN) AF: 0.000365 AC: 19 AN: 51984

Middle Eastern (MID) AF: 0.0176 AC: 73 AN: 4136

European-Non Finnish (NFE) AF: 0.00219 AC: 2193 AN: 1000174

Other (OTH) AF: 0.00710 AC: 395 AN: 55612

GnomAD4 genome AF: 0.0179 AC: 2729 AN: 152256 Hom.: 64 Cov.: 32 AF XY: 0.0175 AC XY: 1302 AN XY: 74448

African (AFR) AF: 0.0550 AC: 2283 AN: 41528

American (AMR) AF: 0.0109 AC: 167 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00891 AC: 43 AN: 4824

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10612

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00272 AC: 185 AN: 68014

Other (OTH) AF: 0.0194 AC: 41 AN: 2114

Alfa AF: 0.0129 Hom.: 6

Bravo AF: 0.0201

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 31, 2018

GeneDx

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	-0.81
CADD	Benign	2.3
DANN	Benign	0.73
PhyloP100		-0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs68121698; hg19: chr16-31202556;