Variant rs34674752 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
SHARPIN	NM_030974.4 linkuse as main transcript	c.880C>T	p.Pro294Ser	missense_variant	6/9	ENST00000398712.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHARPIN	ENST00000398712.7 linkuse as main transcript	c.880C>T	p.Pro294Ser	missense_variant	6/9	1	NM_030974.4	P1	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

GnomAD3 exomes

AF:

0.0306

AC:

7621

AN:

249246

Hom.:

164

AF XY:

0.0306

AC XY:

4138

AN XY:

135274

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 SAS exome

AF:

0.00330

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

Gnomad4 AFR exome

AF:

0.00585

Gnomad4 AMR exome

AF:

0.0209

Gnomad4 ASJ exome

AF:

0.0481

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00349

Gnomad4 FIN exome

AF:

0.0386

Gnomad4 NFE exome

AF:

0.0504

Gnomad4 OTH exome

AF:

0.0387

GnomAD4 genome

AF:

0.0310

AC:

4723

AN:

152290

Hom.:

Cov.:

AF XY:

0.0300

AC XY:

2236

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00881

Gnomad4 AMR

AF:

0.0334

Gnomad4 ASJ

AF:

0.0432

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00414

Gnomad4 FIN

AF:

0.0350

Gnomad4 NFE

AF:

0.0472

Gnomad4 OTH

AF:

0.0431

Alfa

AF:

0.0445

Hom.:

269

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

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

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

MutationTaster

Benign

0.78

N;N

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

Varity_R

0.25

gMVP

0.33

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over