Variant 8-144098948-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_030974.4(SHARPIN):c.1094G>A(p.Arg365His) variant causes a missense change. The variant allele was found at a frequency of 0.00565 in 1,592,062 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0049 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0057 ( 70 hom. )

Consequence

SHARPIN
NM_030974.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.47

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=0.00789538).

BP6

Variant 8-144098948-C-T is Benign according to our data. Variant chr8-144098948-C-T is described in ClinVar as [Benign]. Clinvar id is 710592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00486 (740/152250) while in subpopulation SAS AF= 0.0294 (142/4826). AF 95% confidence interval is 0.0255. There are 6 homozygotes in gnomad4. There are 420 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHARPIN	NM_030974.4 linkuse as main transcript	c.1094G>A	p.Arg365His	missense_variant	8/9	ENST00000398712.7	NP_112236.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHARPIN	ENST00000398712.7 linkuse as main transcript	c.1094G>A	p.Arg365His	missense_variant	8/9	1	NM_030974.4	ENSP00000381698	P1	Q9H0F6-1
SHARPIN	ENST00000359551.6 linkuse as main transcript	c.969G>A	p.Pro323=	synonymous_variant, NMD_transcript_variant	7/8	1		ENSP00000352551		Q9H0F6-2
SHARPIN	ENST00000532536.5 linkuse as main transcript	c.218G>A	p.Arg73His	missense_variant	3/3	3		ENSP00000432355

Frequencies

GnomAD3 genomes

AF:

0.00486

AC:

739

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.00406

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0290

Gnomad FIN

AF:

0.00687

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00494

Gnomad OTH

AF:

0.00813

GnomAD3 exomes

AF:

0.00804

AC:

1816

AN:

225812

Hom.:

AF XY:

0.00900

AC XY:

1110

AN XY:

123378

show subpopulations

Gnomad AFR exome

AF:

0.000670

Gnomad AMR exome

AF:

0.00255

Gnomad ASJ exome

AF:

0.0162

Gnomad EAS exome

AF:

0.000308

Gnomad SAS exome

AF:

0.0288

Gnomad FIN exome

AF:

0.00802

Gnomad NFE exome

AF:

0.00575

Gnomad OTH exome

AF:

0.00884

GnomAD4 exome

AF:

0.00573

AC:

8254

AN:

1439812

Hom.:

Cov.:

AF XY:

0.00643

AC XY:

4606

AN XY:

716506

show subpopulations

Gnomad4 AFR exome

AF:

0.000723

Gnomad4 AMR exome

AF:

0.00258

Gnomad4 ASJ exome

AF:

0.0170

Gnomad4 EAS exome

AF:

0.000152

Gnomad4 SAS exome

AF:

0.0279

Gnomad4 FIN exome

AF:

0.00687

Gnomad4 NFE exome

AF:

0.00412

Gnomad4 OTH exome

AF:

0.00700

GnomAD4 genome

AF:

0.00486

AC:

740

AN:

152250

Hom.:

Cov.:

AF XY:

0.00564

AC XY:

420

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.000698

Gnomad4 AMR

AF:

0.00405

Gnomad4 ASJ

AF:

0.0161

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0294

Gnomad4 FIN

AF:

0.00687

Gnomad4 NFE

AF:

0.00494

Gnomad4 OTH

AF:

0.00805

Alfa

AF:

0.00529

Hom.:

Bravo

AF:

0.00352

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000981

AC:

ESP6500EA

AF:

0.00522

AC:

ExAC

AF:

0.00805

AC:

974

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 02, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.36

T;D

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D

MetaRNN

Benign

0.0079

T;T

MetaSVM

Benign

-0.39

MutationAssessor

Pathogenic

3.1

.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.0

D;D

REVEL

Uncertain

0.45

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

1.0

.;D

Vest4

0.49

MVP

0.73

MPC

0.75

ClinPred

0.048

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.45

gMVP

0.72

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