16-31185051-C-G

Variant names:

• chr16-31185051-C-G
• rs147528034
• NM_004960.4:c.636C>G

Variant summary

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

The NM_004960.4(FUS):​c.636C>G​(p.Asp212Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,611,686 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. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D212D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FUS NM_004960.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.29
• 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: 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 (MetaRNN=0.22560689).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FUS	NM_004960.4	c.636C>G	p.Asp212Glu	missense_variant	Exon 6 of 15	ENST00000254108.12	NP_004951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FUS	ENST00000254108.12	c.636C>G	p.Asp212Glu	missense_variant	Exon 6 of 15	1	NM_004960.4	ENSP00000254108.8

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151646 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460040 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726214

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111116

Other (OTH) AF: 0.0000166 AC: 1 AN: 60324

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151646 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74026

African (AFR) AF: 0.00 AC: 0 AN: 41240

American (AMR) AF: 0.00 AC: 0 AN: 15192

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67914

Other (OTH) AF: 0.00 AC: 0 AN: 2074

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.40	T;.;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.068
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.40	T;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Uncertain	0.26	D
PhyloP100		1.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.046	D;D;D
Sift4G	Benign	0.25	T;T;T
Polyphen		0.43	B;P;.
Vest4		0.37
MutPred		0.30		Loss of MoRF binding (P = 0.0773);.;Loss of MoRF binding (P = 0.0773);
MVP		0.81
MPC		0.18
ClinPred		0.87	D
GERP RS		4.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.095
gMVP		0.54

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: rs147528034; hg19: chr16-31196372;