8-144103543-C-T

Variant names:

• chr8-144103543-C-T
• rs12549149
• NM_030974.4:c.201+10G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_030974.4(SHARPIN):​c.201+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.911 in 1,531,116 control chromosomes in the GnomAD database, including 637,283 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (57715 hom., cov: 35)
  • Exomes 𝑓: 0.92 (579568 hom.)
• Consequence: SHARPIN NM_030974.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.165

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

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 8-144103543-C-T is Benign according to our data. Variant chr8-144103543-C-T is described in ClinVar as [Benign]. Clinvar id is 403433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHARPIN	NM_030974.4	c.201+10G>A		intron_variant	Intron 1 of 8	ENST00000398712.7	NP_112236.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHARPIN	ENST00000398712.7	c.201+10G>A		intron_variant	Intron 1 of 8	1	NM_030974.4	ENSP00000381698.2

Frequencies

GnomAD3 genomes AF: 0.865 AC: 131596 AN: 152136 Hom.: 57694 Cov.: 35

Gnomad AFR AF: 0.710

Gnomad AMI AF: 0.944

Gnomad AMR AF: 0.913

Gnomad ASJ AF: 0.922

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.959

Gnomad FIN AF: 0.928

Gnomad MID AF: 0.882

Gnomad NFE AF: 0.918

Gnomad OTH AF: 0.878

GnomAD2 exomes AF: 0.926 AC: 116966 AN: 126264 AF XY: 0.929

Gnomad AFR exome AF: 0.713

Gnomad AMR exome AF: 0.944

Gnomad ASJ exome AF: 0.925

Gnomad EAS exome AF: 0.995

Gnomad FIN exome AF: 0.919

Gnomad NFE exome AF: 0.914

Gnomad OTH exome AF: 0.925

GnomAD4 exome AF: 0.916 AC: 1262979 AN: 1378866 Hom.: 579568 Cov.: 44 AF XY: 0.918 AC XY: 624576 AN XY: 680234

Gnomad4 AFR exome AF: 0.698 AC: 21774 AN: 31202

Gnomad4 AMR exome AF: 0.941 AC: 33419 AN: 35506

Gnomad4 ASJ exome AF: 0.926 AC: 23209 AN: 25058

Gnomad4 EAS exome AF: 0.996 AC: 35381 AN: 35520

Gnomad4 SAS exome AF: 0.960 AC: 75819 AN: 78988

Gnomad4 FIN exome AF: 0.924 AC: 30877 AN: 33402

Gnomad4 NFE exome AF: 0.915 AC: 986190 AN: 1077358

Gnomad4 Remaining exome AF: 0.911 AC: 52483 AN: 57596

GnomAD4 genome AF: 0.865 AC: 131670 AN: 152250 Hom.: 57715 Cov.: 35 AF XY: 0.869 AC XY: 64661 AN XY: 74436

Gnomad4 AFR AF: 0.710 AC: 0.709557 AN: 0.709557

Gnomad4 AMR AF: 0.913 AC: 0.913149 AN: 0.913149

Gnomad4 ASJ AF: 0.922 AC: 0.921947 AN: 0.921947

Gnomad4 EAS AF: 0.997 AC: 0.997103 AN: 0.997103

Gnomad4 SAS AF: 0.958 AC: 0.958213 AN: 0.958213

Gnomad4 FIN AF: 0.928 AC: 0.927749 AN: 0.927749

Gnomad4 NFE AF: 0.918 AC: 0.917789 AN: 0.917789

Gnomad4 OTH AF: 0.879 AC: 0.879261 AN: 0.879261

Alfa AF: 0.904 Hom.: 6799

Bravo AF: 0.856

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	7.8
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12549149; hg19: chr8-145158446;