Genetic Variant FUS:p.Asp212Asp (chr16-31185051-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_004960.4(FUS):c.636C>T(p.Asp212Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000525 in 1,611,800 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 4 hom. )

Consequence

FUS
NM_004960.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.29

Publications

0 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: 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)

FUS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 16-31185051-C-T is Benign according to our data. Variant chr16-31185051-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 540284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.29 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00242 (368/151760) while in subpopulation AFR AF = 0.00861 (356/41358). AF 95% confidence interval is 0.00787. There are 0 homozygotes in GnomAd4. There are 153 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FUS	NM_004960.4	MANE Select	c.636C>T	p.Asp212Asp	synonymous	Exon 6 of 15	NP_004951.1	P35637-1
FUS	NM_001170634.1		c.633C>T	p.Asp211Asp	synonymous	Exon 6 of 15	NP_001164105.1	P35637-2
FUS	NM_001170937.1		c.624C>T	p.Asp208Asp	synonymous	Exon 6 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.636C>T	p.Asp212Asp	synonymous	Exon 6 of 15	ENSP00000254108.8	P35637-1
FUS	ENST00000380244.8	TSL:1	c.633C>T	p.Asp211Asp	synonymous	Exon 6 of 15	ENSP00000369594.3	P35637-2
FUS	ENST00000566605.5	TSL:1	n.636C>T		non_coding_transcript_exon	Exon 6 of 14	ENSP00000455073.1	H3BNZ4

Frequencies

GnomAD3 genomes

AF:

0.00241

AC:

366

AN:

151642

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00856

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000395

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.00145

GnomAD2 exomes

AF:

0.000744

AC:

181

AN:

243270

AF XY:

0.000508

show subpopulations

Gnomad AFR exome

AF:

0.00987

Gnomad AMR exome

AF:

0.000533

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000185

Gnomad OTH exome

AF:

0.000498

GnomAD4 exome

AF:

0.000327

AC:

478

AN:

1460040

Hom.:

Cov.:

AF XY:

0.000302

AC XY:

219

AN XY:

726214

show subpopulations

African (AFR)

AF:

0.0113

AC:

377

AN:

33454

American (AMR)

AF:

0.000701

AC:

AN:

44236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86170

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53212

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

1111116

Other (OTH)

AF:

0.000680

AC:

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

131

164

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00242

AC:

368

AN:

151760

Hom.:

Cov.:

AF XY:

0.00206

AC XY:

153

AN XY:

74154

show subpopulations

African (AFR)

AF:

0.00861

AC:

356

AN:

41358

American (AMR)

AF:

0.000394

AC:

AN:

15212

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10546

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000442

AC:

AN:

67906

Other (OTH)

AF:

0.00143

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.00270

Hom.:

Bravo

AF:

0.00295

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

4.3

(source)

DANN

Benign

0.81

PhyloP100

1.3

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Mutation Taster

=99/1

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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