NM_030974.4:c.880C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_030974.4(SHARPIN):c.880C>T(p.Pro294Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0421 in 1,614,110 control chromosomes in the GnomAD database, including 1,665 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.031 ( 96 hom., cov: 33)

Exomes 𝑓: 0.043 ( 1569 hom. )

Consequence

SHARPIN
NM_030974.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.64

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002319485).

BP6

Variant 8-144099319-G-A is Benign according to our data. Variant chr8-144099319-G-A is described in ClinVar as Benign. ClinVar VariationId is 403432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.05 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHARPIN	NM_030974.4 link	c.880C>T	p.Pro294Ser	missense_variant	Exon 6 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.880C>T	p.Pro294Ser	missense_variant	Exon 6 of 9	1	NM_030974.4	ENSP00000381698.2		Q9H0F6-1

Frequencies

GnomAD3 genomes

AF:

0.0311

AC:

4725

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00883

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0334

Gnomad ASJ

AF:

0.0432

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.0350

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0472

Gnomad OTH

AF:

0.0435

GnomAD2 exomes

AF:

0.0306

AC:

7621

AN:

249246

AF XY:

0.0306

show subpopulations

Gnomad AFR exome

AF:

0.00575

Gnomad AMR exome

AF:

0.0190

Gnomad ASJ exome

AF:

0.0459

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.0375

Gnomad NFE exome

AF:

0.0469

Gnomad OTH exome

AF:

0.0334

GnomAD4 exome

AF:

0.0432

AC:

63214

AN:

1461820

Hom.:

1569

Cov.:

AF XY:

0.0424

AC XY:

30803

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.00585

AC:

196

AN:

33480

American (AMR)

AF:

0.0209

AC:

935

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0481

AC:

1256

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00349

AC:

301

AN:

86258

European-Finnish (FIN)

AF:

0.0386

AC:

2061

AN:

53394

Middle Eastern (MID)

AF:

0.0165

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0504

AC:

56034

AN:

1111990

Other (OTH)

AF:

0.0387

AC:

2335

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

3979

7959

11938

15918

19897

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2026

4052

6078

8104

10130

<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:

0.0310

AC:

4723

AN:

152290

Hom.:

Cov.:

AF XY:

0.0300

AC XY:

2236

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00881

AC:

366

AN:

41554

American (AMR)

AF:

0.0334

AC:

511

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0432

AC:

150

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5188

South Asian (SAS)

AF:

0.00414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0350

AC:

372

AN:

10622

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0472

AC:

3207

AN:

68010

Other (OTH)

AF:

0.0431

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

239

478

717

956

1195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.0419

Hom.:

369

Bravo

AF:

0.0297

TwinsUK

AF:

0.0407

AC:

151

ALSPAC

AF:

0.0441

AC:

170

ESP6500AA

AF:

0.00738

AC:

ESP6500EA

AF:

0.0438

AC:

370

ExAC

AF:

0.0299

AC:

3621

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0510

EpiControl

AF:

0.0494

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

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0094

T;T

Eigen

Benign

-0.0063

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.80

T;T

MetaRNN

Benign

0.0023

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

.;L

PhyloP100

2.6

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.32

N;N

REVEL

Benign

0.055

Sift

Benign

0.61

T;T

Sift4G

Benign

0.44

T;T

Polyphen

0.45

.;B

Vest4

0.13

MPC

0.57

ClinPred

0.016

GERP RS

4.6

PromoterAI

-0.0096

Neutral

(source)

Varity_R

0.25

gMVP

0.33

Mutation Taster

=91/9

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