Variant 8-144098924-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_030974.4(SHARPIN):c.1118C>T(p.Thr373Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,442,638 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SHARPIN
NM_030974.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.96

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHARPIN	NM_030974.4 link	c.1118C>T	p.Thr373Ile	missense_variant	Exon 8 of 9	ENST00000398712.7	NP_112236.3	Q9H0F6-1Q6PJD5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SHARPIN	ENST00000398712.7 link	c.1118C>T	p.Thr373Ile	missense_variant	Exon 8 of 9	1	NM_030974.4	ENSP00000381698.2	Q9H0F6-1
SHARPIN	ENST00000359551.6 link	n.*12C>T		non_coding_transcript_exon_variant	Exon 7 of 8	1		ENSP00000352551.6	Q9H0F6-2
SHARPIN	ENST00000359551.6 link	n.*12C>T		3_prime_UTR_variant	Exon 7 of 8	1		ENSP00000352551.6	Q9H0F6-2
SHARPIN	ENST00000532536.5 link	c.242C>T	p.Thr81Ile	missense_variant	Exon 3 of 3	3		ENSP00000432355.1	H0YCU2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1442638

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

717830

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000240

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1118C>T (p.T373I) alteration is located in exon 8 (coding exon 8) of the SHARPIN gene. This alteration results from a C to T substitution at nucleotide position 1118, causing the threonine (T) at amino acid position 373 to be replaced by an isoleucine (I). 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

0.58

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

T;T

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

T;D

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.67

D;D

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.5

.;M

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-4.1

D;D

REVEL

Uncertain

0.37

Sift

Benign

0.047

D;D

Sift4G

Uncertain

0.050

T;D

Polyphen

1.0

.;D

Vest4

0.55

MutPred

0.40

.;Loss of phosphorylation at T373 (P = 0.0323);

MVP

0.76

MPC

0.69

ClinPred

0.98

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.25

gMVP

0.68

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over