ENST00000380244.8:c.*770G>C

Variant names:

• chr16-31192208-G-C
• rs4889537
• ENST00000380244.8:c.*770G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000380244.8(FUS):​c.*770G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 526,328 control chromosomes in the GnomAD database, including 28,666 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.26 (6043 hom., cov: 31)
  • Exomes 𝑓: 0.33 (22623 hom.)
• Consequence: FUS ENST00000380244.8 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0150
• Publications: 19 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: Illumina, Orphanet
• 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: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 16-31192208-G-C is Benign according to our data. Variant chr16-31192208-G-C is described in ClinVar as Benign. ClinVar VariationId is 319004.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000380244.8. 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_001170634.1		c.*770G>C		3_prime_UTR	Exon 15 of 15	NP_001164105.1	P35637-2
	FUS	NM_001170937.1		c.*770G>C		3_prime_UTR	Exon 15 of 15	NP_001164408.1	Q13344
	FUS	NR_028388.2		n.2421G>C		non_coding_transcript_exon	Exon 14 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FUS	ENST00000380244.8	TSL:1	c.*770G>C		3_prime_UTR	Exon 15 of 15	ENSP00000369594.3	P35637-2

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38803 AN: 151904 Hom.: 6041 Cov.: 31

Gnomad AFR AF: 0.0788

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.241

Gnomad SAS AF: 0.530

Gnomad FIN AF: 0.377

Gnomad MID AF: 0.172

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.234

GnomAD2 exomes AF: 0.336 AC: 43057 AN: 128058 AF XY: 0.348

Gnomad AFR exome AF: 0.0673

Gnomad AMR exome AF: 0.374

Gnomad ASJ exome AF: 0.197

Gnomad EAS exome AF: 0.251

Gnomad FIN exome AF: 0.388

Gnomad NFE exome AF: 0.309

Gnomad OTH exome AF: 0.313

GnomAD4 exome AF: 0.330 AC: 123567 AN: 374306 Hom.: 22623 Cov.: 0 AF XY: 0.345 AC XY: 70785 AN XY: 205448

African (AFR) AF: 0.0713 AC: 856 AN: 11998

American (AMR) AF: 0.369 AC: 10888 AN: 29488

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 3041 AN: 15370

East Asian (EAS) AF: 0.207 AC: 4060 AN: 19584

South Asian (SAS) AF: 0.507 AC: 30572 AN: 60280

European-Finnish (FIN) AF: 0.382 AC: 4752 AN: 12436

Middle Eastern (MID) AF: 0.215 AC: 343 AN: 1592

European-Non Finnish (NFE) AF: 0.310 AC: 63145 AN: 203388

Other (OTH) AF: 0.293 AC: 5910 AN: 20170

GnomAD4 genome AF: 0.255 AC: 38812 AN: 152022 Hom.: 6043 Cov.: 31 AF XY: 0.263 AC XY: 19516 AN XY: 74306

African (AFR) AF: 0.0786 AC: 3264 AN: 41522

American (AMR) AF: 0.329 AC: 5013 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 648 AN: 3472

East Asian (EAS) AF: 0.240 AC: 1238 AN: 5150

South Asian (SAS) AF: 0.530 AC: 2556 AN: 4822

European-Finnish (FIN) AF: 0.377 AC: 3976 AN: 10542

Middle Eastern (MID) AF: 0.164 AC: 48 AN: 292

European-Non Finnish (NFE) AF: 0.314 AC: 21357 AN: 67940

Other (OTH) AF: 0.238 AC: 503 AN: 2112

Alfa AF: 0.211 Hom.: 785

Bravo AF: 0.236

Asia WGS AF: 0.380 AC: 1320 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Amyotrophic lateral sclerosis type 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.4
DANN	Benign	0.78
PhyloP100		0.015

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4889537;

hg19: chr16-31203529;