chr8-144098981-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_030974.4(SHARPIN):​c.1061G>A​(p.Cys354Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000649 in 1,603,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

SHARPIN
NM_030974.4 missense

Scores

11
6
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.12
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_pathogenic. Variant got 8 ACMG points.

PM1
In a mutagenesis_site Abolishes binding to ubiquitin without affecting interaction with RNF31; when associated with S-357. (size 0) in uniprot entity SHRPN_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SHARPINNM_030974.4 linkuse as main transcriptc.1061G>A p.Cys354Tyr missense_variant 8/9 ENST00000398712.7 NP_112236.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SHARPINENST00000398712.7 linkuse as main transcriptc.1061G>A p.Cys354Tyr missense_variant 8/91 NM_030974.4 ENSP00000381698 P1Q9H0F6-1
SHARPINENST00000359551.6 linkuse as main transcriptc.936G>A p.Leu312= synonymous_variant, NMD_transcript_variant 7/81 ENSP00000352551 Q9H0F6-2
SHARPINENST00000532536.5 linkuse as main transcriptc.185G>A p.Cys62Tyr missense_variant 3/33 ENSP00000432355

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152152
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000293
AC:
7
AN:
238714
Hom.:
0
AF XY:
0.0000230
AC XY:
3
AN XY:
130184
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000638
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000710
AC:
103
AN:
1451276
Hom.:
0
Cov.:
31
AF XY:
0.0000581
AC XY:
42
AN XY:
722342
show subpopulations
Gnomad4 AFR exome
AF:
0.0000306
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000911
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152152
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74316
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000772
Hom.:
0
Bravo
AF:
0.0000151

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 GeneticsFeb 15, 2023The c.1061G>A (p.C354Y) alteration is located in exon 8 (coding exon 8) of the SHARPIN gene. This alteration results from a G to A substitution at nucleotide position 1061, causing the cysteine (C) at amino acid position 354 to be replaced by a tyrosine (Y). 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
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
27
DANN
Uncertain
0.98
DEOGEN2
Benign
0.32
T;D
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.88
D;D
M_CAP
Pathogenic
0.92
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
0.98
D
MutationAssessor
Pathogenic
3.2
.;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-11
D;D
REVEL
Pathogenic
0.93
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0020
D;D
Polyphen
1.0
.;D
Vest4
0.95
MVP
0.99
MPC
0.89
ClinPred
0.99
D
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.92
gMVP
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs925928246; hg19: chr8-145153884; COSMIC: COSV59644097; COSMIC: COSV59644097; API