chr8-144099319-G-A

Position:

• chr8-144099319-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_030974.4(SHARPIN):​c.880C>T​(p.Pro294Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0421 in 1,614,110 control chromosomes in the GnomAD database, including 1,665 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.031 (96 hom., cov: 33)
  • Exomes 𝑓: 0.043 (1569 hom.)
• Consequence: SHARPIN NM_030974.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.64

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002319485).
• BP6: Variant 8-144099319-G-A is Benign according to our data. Variant chr8-144099319-G-A is described in ClinVar as [Benign]. Clinvar id is 403432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.05 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHARPIN	NM_030974.4	c.880C>T	p.Pro294Ser	missense_variant	6/9	ENST00000398712.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHARPIN	ENST00000398712.7	c.880C>T	p.Pro294Ser	missense_variant	6/9	1	NM_030974.4	P1

Frequencies

GnomAD3 genomes AF: 0.0311 AC: 4725 AN: 152172 Hom.: 96 Cov.: 33

Gnomad AFR AF: 0.00883

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0334

Gnomad ASJ AF: 0.0432

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0350

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0472

Gnomad OTH AF: 0.0435

GnomAD3 exomes AF: 0.0306 AC: 7621 AN: 249246 Hom.: 164 AF XY: 0.0306 AC XY: 4138 AN XY: 135274

Gnomad AFR exome AF: 0.00575

Gnomad AMR exome AF: 0.0190

Gnomad ASJ exome AF: 0.0459

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00330

Gnomad FIN exome AF: 0.0375

Gnomad NFE exome AF: 0.0469

Gnomad OTH exome AF: 0.0334

GnomAD4 exome AF: 0.0432 AC: 63214 AN: 1461820 Hom.: 1569 Cov.: 32 AF XY: 0.0424 AC XY: 30803 AN XY: 727216

Gnomad4 AFR exome AF: 0.00585

Gnomad4 AMR exome AF: 0.0209

Gnomad4 ASJ exome AF: 0.0481

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00349

Gnomad4 FIN exome AF: 0.0386

Gnomad4 NFE exome AF: 0.0504

Gnomad4 OTH exome AF: 0.0387

GnomAD4 genome AF: 0.0310 AC: 4723 AN: 152290 Hom.: 96 Cov.: 33 AF XY: 0.0300 AC XY: 2236 AN XY: 74462

Gnomad4 AFR AF: 0.00881

Gnomad4 AMR AF: 0.0334

Gnomad4 ASJ AF: 0.0432

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.0350

Gnomad4 NFE AF: 0.0472

Gnomad4 OTH AF: 0.0431

Alfa AF: 0.0445 Hom.: 269

Bravo AF: 0.0297

TwinsUK AF: 0.0407 AC: 151

ALSPAC AF: 0.0441 AC: 170

ESP6500AA AF: 0.00738 AC: 31

ESP6500EA AF: 0.0438 AC: 370

ExAC AF: 0.0299 AC: 3621

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0510

EpiControl AF: 0.0494

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0094	T;T
Eigen	Benign	-0.0063
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	T;T
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;L
MutationTaster	Benign	0.78	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.32	N;N
REVEL	Benign	0.055
Sift	Benign	0.61	T;T
Sift4G	Benign	0.44	T;T
Polyphen		0.45	.;B
Vest4		0.13
MPC		0.57
ClinPred		0.016	T
GERP RS		4.6
Varity_R		0.25
gMVP		0.33

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

Other links and lift over

dbSNP: rs34674752; hg19: chr8-145154222;