rs780606789

Variant names:

• chr16-31191546-C-A
• rs780606789
• ENST00000566605.5:n.*862C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-31191546-C-A
• chr16-31191546-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000566605.5(FUS):​n.*862C>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000935 in 1,069,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 9.3e-7 (0 hom.)
• Consequence: FUS ENST00000566605.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0250
• Publications: 4 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000566605.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FUS	NM_004960.4	MANE Select	c.*108C>A		3_prime_UTR	Exon 15 of 15	NP_004951.1
	FUS	NR_028388.2		n.1759C>A		non_coding_transcript_exon	Exon 14 of 14
	FUS	NM_001170634.1		c.*108C>A		3_prime_UTR	Exon 15 of 15	NP_001164105.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FUS	ENST00000566605.5	TSL:1	n.*862C>A		non_coding_transcript_exon	Exon 14 of 14	ENSP00000455073.1
	FUS	ENST00000254108.12	TSL:1 MANE Select	c.*108C>A		3_prime_UTR	Exon 15 of 15	ENSP00000254108.8
	FUS	ENST00000380244.8	TSL:1	c.*108C>A		3_prime_UTR	Exon 15 of 15	ENSP00000369594.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 9.35e-7 AC: 1 AN: 1069728 Hom.: 0 Cov.: 14 AF XY: 0.00000183 AC XY: 1 AN XY: 547836

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25588

American (AMR) AF: 0.00 AC: 0 AN: 40366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23492

East Asian (EAS) AF: 0.00 AC: 0 AN: 36836

South Asian (SAS) AF: 0.0000130 AC: 1 AN: 76668

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51924

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3898

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 763718

Other (OTH) AF: 0.00 AC: 0 AN: 47238

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	11
DANN	Benign	0.77
PhyloP100		0.025
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs780606789; hg19: chr16-31202867;