chr16-31184918-T-C

Variant names:

• chr16-31184918-T-C
• rs74015090
• NM_004960.4:c.524-21T>C

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.524-21T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,594,272 control chromosomes in the GnomAD database, including 1,072 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.048 (555 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (517 hom.)
• Consequence: FUS NM_004960.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.33
• Publications: 0 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-31184918-T-C is Benign according to our data. Variant chr16-31184918-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FUS	NM_004960.4	c.524-21T>C		intron_variant	Intron 5 of 14	ENST00000254108.12	NP_004951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FUS	ENST00000254108.12	c.524-21T>C		intron_variant	Intron 5 of 14	1	NM_004960.4	ENSP00000254108.8

Frequencies

GnomAD3 genomes AF: 0.0477 AC: 7237 AN: 151844 Hom.: 551 Cov.: 32

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0199

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00955

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00303

Gnomad OTH AF: 0.0330

GnomAD2 exomes AF: 0.0148 AC: 3662 AN: 247732 AF XY: 0.0118

Gnomad AFR exome AF: 0.165

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.000797

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000188

Gnomad NFE exome AF: 0.00294

Gnomad OTH exome AF: 0.0102

GnomAD4 exome AF: 0.00706 AC: 10188 AN: 1442312 Hom.: 517 Cov.: 30 AF XY: 0.00674 AC XY: 4844 AN XY: 718480

African (AFR) AF: 0.166 AC: 5496 AN: 33050

American (AMR) AF: 0.0110 AC: 490 AN: 44440

Ashkenazi Jewish (ASJ) AF: 0.000462 AC: 12 AN: 25994

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39612

South Asian (SAS) AF: 0.00837 AC: 717 AN: 85614

European-Finnish (FIN) AF: 0.000358 AC: 19 AN: 53102

Middle Eastern (MID) AF: 0.0216 AC: 124 AN: 5730

European-Non Finnish (NFE) AF: 0.00227 AC: 2483 AN: 1095064

Other (OTH) AF: 0.0141 AC: 844 AN: 59706

GnomAD4 genome AF: 0.0479 AC: 7275 AN: 151960 Hom.: 555 Cov.: 32 AF XY: 0.0458 AC XY: 3406 AN XY: 74312

African (AFR) AF: 0.160 AC: 6633 AN: 41364

American (AMR) AF: 0.0199 AC: 304 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00956 AC: 46 AN: 4812

European-Finnish (FIN) AF: 0.000284 AC: 3 AN: 10556

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

European-Non Finnish (NFE) AF: 0.00303 AC: 206 AN: 67984

Other (OTH) AF: 0.0341 AC: 72 AN: 2110

Alfa AF: 0.0300 Hom.: 82

Bravo AF: 0.0536

Asia WGS AF: 0.0180 AC: 62 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 31, 2018

GeneDx

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

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely 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	-0.82
CADD	Benign	0.79
DANN	Benign	0.28
PhyloP100		-1.3
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs74015090; hg19: chr16-31196239;