dbSNP rs11136254: SHARPIN:p.Arg52Arg (chr8-144103600-G-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_030974.4(SHARPIN):c.154C>A(p.Arg52Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.911 in 1,531,066 control chromosomes in the GnomAD database, including 637,285 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.86 ( 57704 hom., cov: 35)

Exomes 𝑓: 0.92 ( 579581 hom. )

Consequence

SHARPIN
NM_030974.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.788

Publications

19 publications found

Variant links:

Genes affected

SHARPIN (HGNC:25321): (SHANK associated RH domain interactor) Enables polyubiquitin modification-dependent protein binding activity. Involved in protein linear polyubiquitination and regulation of signal transduction. Located in cytosol. Part of LUBAC complex. [provided by Alliance of Genome Resources, Apr 2022]

SHARPIN Gene-Disease associations (from GenCC):

autoinflammation with episodic fever and immune dysregulation
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

SHARPIN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 8-144103600-G-T is Benign according to our data. Variant chr8-144103600-G-T is described in ClinVar as Benign. ClinVar VariationId is 403434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.788 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHARPIN	NM_030974.4 link	c.154C>A	p.Arg52Arg	synonymous_variant	Exon 1 of 9	ENST00000398712.7	NP_112236.3	Q9H0F6-1Q6PJD5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHARPIN	ENST00000398712.7 link	c.154C>A	p.Arg52Arg	synonymous_variant	Exon 1 of 9	1	NM_030974.4	ENSP00000381698.2		Q9H0F6-1

Frequencies

GnomAD3 genomes

AF:

0.865

AC:

131569

AN:

152120

Hom.:

57681

Cov.:

show subpopulations

Gnomad AFR

AF:

0.709

Gnomad AMI

AF:

0.942

Gnomad AMR

AF:

0.912

Gnomad ASJ

AF:

0.922

Gnomad EAS

AF:

0.997

Gnomad SAS

AF:

0.959

Gnomad FIN

AF:

0.928

Gnomad MID

AF:

0.882

Gnomad NFE

AF:

0.918

Gnomad OTH

AF:

0.878

GnomAD2 exomes

AF:

0.927

AC:

117876

AN:

127126

AF XY:

0.930

show subpopulations

Gnomad AFR exome

AF:

0.719

Gnomad AMR exome

AF:

0.944

Gnomad ASJ exome

AF:

0.926

Gnomad EAS exome

AF:

0.994

Gnomad FIN exome

AF:

0.919

Gnomad NFE exome

AF:

0.914

Gnomad OTH exome

AF:

0.925

GnomAD4 exome

AF:

0.916

AC:

1262982

AN:

1378828

Hom.:

579581

Cov.:

AF XY:

0.918

AC XY:

624457

AN XY:

680092

show subpopulations

African (AFR)

AF:

0.698

AC:

21717

AN:

31106

American (AMR)

AF:

0.941

AC:

33538

AN:

35628

Ashkenazi Jewish (ASJ)

AF:

0.926

AC:

23206

AN:

25054

East Asian (EAS)

AF:

0.996

AC:

35422

AN:

35562

South Asian (SAS)

AF:

0.960

AC:

75873

AN:

79038

European-Finnish (FIN)

AF:

0.924

AC:

30902

AN:

33430

Middle Eastern (MID)

AF:

0.904

AC:

3807

AN:

4210

European-Non Finnish (NFE)

AF:

0.915

AC:

986068

AN:

1077246

Other (OTH)

AF:

0.911

AC:

52449

AN:

57554

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

5824

11649

17473

23298

29122

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21100

42200

63300

84400

105500

<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:

0.865

AC:

131647

AN:

152238

Hom.:

57704

Cov.:

AF XY:

0.869

AC XY:

64655

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.709

AC:

29453

AN:

41520

American (AMR)

AF:

0.913

AC:

13966

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.922

AC:

3201

AN:

3472

East Asian (EAS)

AF:

0.997

AC:

5159

AN:

5174

South Asian (SAS)

AF:

0.958

AC:

4630

AN:

4832

European-Finnish (FIN)

AF:

0.928

AC:

9848

AN:

10612

Middle Eastern (MID)

AF:

0.880

AC:

257

AN:

292

European-Non Finnish (NFE)

AF:

0.918

AC:

62415

AN:

68008

Other (OTH)

AF:

0.880

AC:

1859

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

872

1744

2617

3489

4361

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

890

1780

2670

3560

4450

<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:

0.891

Hom.:

18391

Bravo

AF:

0.855

Asia WGS

AF:

0.963

AC:

3346

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.88

PhyloP100

0.79

PromoterAI

0.042

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over