8-144099933-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030974.4(SHARPIN):c.513G>C(p.Glu171Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000436 in 1,377,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: SHARPIN NM_030974.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.01

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1432805).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHARPIN	NM_030974.4	c.513G>C	p.Glu171Asp	missense_variant	3/9	ENST00000398712.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHARPIN	ENST00000398712.7	c.513G>C	p.Glu171Asp	missense_variant	3/9	1	NM_030974.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000436 AC: 6 AN: 1377056 Hom.: 0 Cov.: 40 AF XY: 0.00000439 AC XY: 3 AN XY: 683790

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000174

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.48e-7

Gnomad4 OTH exome AF: 0.0000182

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.513G>C (p.E171D) alteration is located in exon 3 (coding exon 3) of the SHARPIN gene. This alteration results from a G to C substitution at nucleotide position 513, causing the glutamic acid (E) at amino acid position 171 to be replaced by an aspartic acid (D). 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	0.16
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.052
Sift	Uncertain	0.028	D
Sift4G	Benign	0.34	T
Polyphen		0.53	P
Vest4		0.23
MutPred		0.092		Loss of glycosylation at T170 (P = 0.2984);
MVP		0.24
MPC		0.31
ClinPred		0.24	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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

Other links and lift over

dbSNP: rs1218430063; hg19: chr8-145154836;