chr16-31184934-C-T

Variant names:

• chr16-31184934-C-T
• rs73530287
• NM_004960.4:c.524-5C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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: Splicing: ADA: 0.00005232
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0820
• Publications: 2 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: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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=-0.78).
• BP6: Variant 16-31184934-C-T is Benign according to our data. Variant chr16-31184934-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 318985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 41 AD,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004960.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FUS	NM_004960.4	MANE Select	c.524-5C>T		splice_region intron	N/A	NP_004951.1	P35637-1
	FUS	NM_001170634.1		c.521-5C>T		splice_region intron	N/A	NP_001164105.1	P35637-2
	FUS	NM_001170937.1		c.512-5C>T		splice_region intron	N/A	NP_001164408.1	Q13344

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FUS	ENST00000254108.12	TSL:1 MANE Select	c.524-5C>T		splice_region intron	N/A	ENSP00000254108.8	P35637-1
	FUS	ENST00000380244.8	TSL:1	c.521-5C>T		splice_region intron	N/A	ENSP00000369594.3	P35637-2
	FUS	ENST00000566605.5	TSL:1	n.524-5C>T		splice_region intron	N/A	ENSP00000455073.1	H3BNZ4

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2080 AN: 150984 Hom.: 41 Cov.: 32

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

GnomAD2 exomes AF: 0.00366 AC: 910 AN: 248322 AF XY: 0.00270

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 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

African (AFR) AF: 0.0491 AC: 1640 AN: 33378

American (AMR) AF: 0.00274 AC: 122 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.0000581 AC: 5 AN: 86076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.0000280 AC: 31 AN: 1108812

Other (OTH) AF: 0.00294 AC: 177 AN: 60248

GnomAD4 genome AF: 0.0138 AC: 2080 AN: 151100 Hom.: 41 Cov.: 32 AF XY: 0.0132 AC XY: 974 AN XY: 73716

African (AFR) AF: 0.0481 AC: 1975 AN: 41086

American (AMR) AF: 0.00495 AC: 75 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10266

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67880

Other (OTH) AF: 0.0100 AC: 21 AN: 2096

Alfa AF: 0.00610 Hom.: 17

Bravo AF: 0.0157

Asia WGS AF: 0.00289 AC: 11 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Amyotrophic lateral sclerosis type 6 (1)
-	-	1	Amyotrophic lateral sclerosis type 6;C3539195:Tremor, hereditary essential, 4 (1)
-	-	1	FUS-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.88
DANN	Benign	0.57
PhyloP100		0.082
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs73530287; hg19: chr16-31196255;