chr16-31190129-C-A

Variant names:

• chr16-31190129-C-A
• rs61733965
• NM_004960.4:c.1156C>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004960.4(FUS):​c.1156C>A​(p.Arg386Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,613,930 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (42 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (48 hom.)
• Consequence: FUS NM_004960.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.63
• Publications: 3 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.2).
• BP6: Variant 16-31190129-C-A is Benign according to our data. Variant chr16-31190129-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 318990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.63 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0138 (2095/152074) while in subpopulation AFR AF = 0.048 (1991/41446). AF 95% confidence interval is 0.0463. There are 42 homozygotes in GnomAd4. There are 980 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 42 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.1156C>A	p.Arg386Arg	synonymous	Exon 11 of 15	NP_004951.1	P35637-1
	FUS	NM_001170634.1		c.1153C>A	p.Arg385Arg	synonymous	Exon 11 of 15	NP_001164105.1	P35637-2
	FUS	NM_001170937.1		c.1144C>A	p.Arg382Arg	synonymous	Exon 11 of 15	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.1156C>A	p.Arg386Arg	synonymous	Exon 11 of 15	ENSP00000254108.8	P35637-1
	FUS	ENST00000380244.8	TSL:1	c.1153C>A	p.Arg385Arg	synonymous	Exon 11 of 15	ENSP00000369594.3	P35637-2
	FUS	ENST00000566605.5	TSL:1	n.*329C>A		non_coding_transcript_exon	Exon 10 of 14	ENSP00000455073.1	H3BNZ4

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2095 AN: 151956 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.0482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00498

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: 0.0000735

Gnomad OTH AF: 0.0101

GnomAD2 exomes AF: 0.00365 AC: 918 AN: 251356 AF XY: 0.00269

Gnomad AFR exome AF: 0.0491

Gnomad AMR exome AF: 0.00269

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00136 AC: 1983 AN: 1461856 Hom.: 48 Cov.: 33 AF XY: 0.00115 AC XY: 839 AN XY: 727224

African (AFR) AF: 0.0492 AC: 1648 AN: 33480

American (AMR) AF: 0.00277 AC: 124 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5756

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1112002

Other (OTH) AF: 0.00293 AC: 177 AN: 60390

GnomAD4 genome AF: 0.0138 AC: 2095 AN: 152074 Hom.: 42 Cov.: 32 AF XY: 0.0132 AC XY: 980 AN XY: 74354

African (AFR) AF: 0.0480 AC: 1991 AN: 41446

American (AMR) AF: 0.00498 AC: 76 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67986

Other (OTH) AF: 0.00996 AC: 21 AN: 2108

Alfa AF: 0.00573 Hom.: 17

Bravo AF: 0.0157

Asia WGS AF: 0.00289 AC: 11 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

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	-0.20
CADD	Benign	14
DANN	Benign	0.62
PhyloP100		1.6
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
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: rs61733965; hg19: chr16-31201450;