dbSNP rs144853447: FUS:p.Tyr66Tyr (chr16-31183865-T-C) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS1

The NM_004960.4(FUS):c.198T>C(p.Tyr66Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000676 in 1,614,188 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00069 ( 1 hom. )

Consequence

FUS
NM_004960.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.03

Publications

5 publications found

Variant links:

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

FUS links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_004960.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 16-31183865-T-C is Benign according to our data. Variant chr16-31183865-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 540282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.03 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000532 (81/152300) while in subpopulation NFE AF = 0.000764 (52/68026). AF 95% confidence interval is 0.000599. There are 0 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FUS	NM_004960.4	MANE Select	c.198T>C	p.Tyr66Tyr	synonymous	Exon 4 of 15	NP_004951.1	P35637-1
FUS	NM_001170634.1		c.195T>C	p.Tyr65Tyr	synonymous	Exon 4 of 15	NP_001164105.1	P35637-2
FUS	NM_001170937.1		c.198T>C	p.Tyr66Tyr	synonymous	Exon 4 of 15	NP_001164408.1	Q13344

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FUS	ENST00000254108.12	TSL:1 MANE Select	c.198T>C	p.Tyr66Tyr	synonymous	Exon 4 of 15	ENSP00000254108.8	P35637-1
FUS	ENST00000380244.8	TSL:1	c.195T>C	p.Tyr65Tyr	synonymous	Exon 4 of 15	ENSP00000369594.3	P35637-2
FUS	ENST00000566605.5	TSL:1	n.198T>C		non_coding_transcript_exon	Exon 4 of 14	ENSP00000455073.1	H3BNZ4

Frequencies

GnomAD3 genomes

AF:

0.000532

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000764

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000672

AC:

169

AN:

251494

AF XY:

0.000633

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00124

Gnomad ASJ exome

AF:

0.000893

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000835

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.000691

AC:

1010

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000707

AC XY:

514

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33480

American (AMR)

AF:

0.00127

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00111

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000792

AC:

881

AN:

1112006

Other (OTH)

AF:

0.000480

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

116

175

233

291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000532

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41542

American (AMR)

AF:

0.000588

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000764

AC:

AN:

68026

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000667

Hom.:

Bravo

AF:

0.000525

EpiCase

AF:

0.00120

EpiControl

AF:

0.00101

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Amyotrophic lateral sclerosis type 6 (1)

Amyotrophic lateral sclerosis type 6;C3539195:Tremor, hereditary essential, 4 (1)

FUS-related disorder (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

7.4

(source)

DANN

Benign

0.65

PhyloP100

1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=79/21

polymorphism

(source)

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over