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GeneBe

8-144099794-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_030974.4(SHARPIN):c.568G>C(p.Gly190Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000205 in 1,612,840 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00045 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

SHARPIN
NM_030974.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.714
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.017593503).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SHARPINNM_030974.4 linkuse as main transcriptc.568G>C p.Gly190Arg missense_variant 4/9 ENST00000398712.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SHARPINENST00000398712.7 linkuse as main transcriptc.568G>C p.Gly190Arg missense_variant 4/91 NM_030974.4 P1Q9H0F6-1

Frequencies

GnomAD3 genomes
AF:
0.000453
AC:
69
AN:
152170
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00399
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.000194
AC:
48
AN:
247980
Hom.:
0
AF XY:
0.000171
AC XY:
23
AN XY:
134842
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000783
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000168
Gnomad OTH exome
AF:
0.000331
GnomAD4 exome
AF:
0.000179
AC:
262
AN:
1460670
Hom.:
0
Cov.:
33
AF XY:
0.000175
AC XY:
127
AN XY:
726706
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.000626
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000208
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.000453
AC:
69
AN:
152170
Hom.:
1
Cov.:
33
AF XY:
0.000686
AC XY:
51
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00399
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.000956
Alfa
AF:
0.0000794
Hom.:
0
Bravo
AF:
0.000416
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000120
AC:
1
ExAC
AF:
0.000107
AC:
13
EpiCase
AF:
0.000218
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 14, 2023The c.568G>C (p.G190R) alteration is located in exon 4 (coding exon 4) of the SHARPIN gene. This alteration results from a G to C substitution at nucleotide position 568, causing the glycine (G) at amino acid position 190 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.54
T
BayesDel_noAF
Benign
-0.63
Cadd
Benign
8.1
Dann
Benign
0.73
DEOGEN2
Benign
0.043
T
Eigen
Benign
-0.97
Eigen_PC
Benign
-0.99
FATHMM_MKL
Benign
0.26
N
LIST_S2
Benign
0.48
T
M_CAP
Benign
0.0052
T
MetaRNN
Benign
0.018
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.95
L
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-0.72
N
REVEL
Benign
0.010
Sift
Benign
0.60
T
Sift4G
Benign
0.19
T
Polyphen
0.022
B
Vest4
0.23
MutPred
0.30
Gain of MoRF binding (P = 0.0262);
MVP
0.24
MPC
0.20
ClinPred
0.012
T
GERP RS
0.20
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.0
Varity_R
0.13
gMVP
0.51

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.

Other links and lift over

dbSNP: rs200702253; hg19: chr8-145154697; COSMIC: COSV59362819; COSMIC: COSV59362819; API