chr8-144098981-C-T
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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
NM_030974.4 missense
Scores
11
6
2
Clinical Significance
Conservation
PhyloP100: 6.12
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]
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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 |
---|---|---|---|---|---|---|---|---|
SHARPIN | NM_030974.4 | c.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 |
---|---|---|---|---|---|---|---|---|---|---|
SHARPIN | ENST00000398712.7 | c.1061G>A | p.Cys354Tyr | missense_variant | 8/9 | 1 | NM_030974.4 | ENSP00000381698 | P1 | |
SHARPIN | ENST00000359551.6 | c.936G>A | p.Leu312= | synonymous_variant, NMD_transcript_variant | 7/8 | 1 | ENSP00000352551 | |||
SHARPIN | ENST00000532536.5 | c.185G>A | p.Cys62Tyr | missense_variant | 3/3 | 3 | ENSP00000432355 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152152Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000293 AC: 7AN: 238714Hom.: 0 AF XY: 0.0000230 AC XY: 3AN XY: 130184
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GnomAD4 exome AF: 0.0000710 AC: 103AN: 1451276Hom.: 0 Cov.: 31 AF XY: 0.0000581 AC XY: 42AN XY: 722342
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152152Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74316
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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 submitter | clinical testing | Ambry Genetics | Feb 15, 2023 | The 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;M
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
1.0
.;D
Vest4
0.95
MVP
MPC
0.89
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at