rs11136254

chr8-144103600-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_030974.4(SHARPIN):c.154C>A(p.Arg52=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.911 in 1,531,066 control chromosomes in the GnomAD database, including 637,285 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.86 (57704 hom., cov: 35)
  • Exomes 𝑓: 0.92 (579581 hom.)
• Consequence: SHARPIN NM_030974.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.788

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 8-144103600-G-T is Benign according to our data. Variant chr8-144103600-G-T is described in ClinVar as [Benign]. Clinvar id is 403434.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.788 with no splicing effect.
• 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/exons	MANE	UniProt
SHARPIN	NM_030974.4	c.154C>A	p.Arg52=	synonymous_variant	1/9	ENST00000398712.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHARPIN	ENST00000398712.7	c.154C>A	p.Arg52=	synonymous_variant	1/9	1	NM_030974.4	P1

Frequencies

GnomAD3 genomes AF: 0.865 AC: 131569 AN: 152120 Hom.: 57681 Cov.: 35

Gnomad AFR AF: 0.709

Gnomad AMI AF: 0.942

Gnomad AMR AF: 0.912

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

GnomAD3 exomes AF: 0.927 AC: 117876 AN: 127126 Hom.: 54829 AF XY: 0.930 AC XY: 64811 AN XY: 69688

Gnomad AFR exome AF: 0.719

Gnomad AMR exome AF: 0.944

Gnomad ASJ exome AF: 0.926

Gnomad EAS exome AF: 0.994

Gnomad SAS exome AF: 0.961

Gnomad FIN exome AF: 0.919

Gnomad NFE exome AF: 0.914

Gnomad OTH exome AF: 0.925

GnomAD4 exome AF: 0.916 AC: 1262982 AN: 1378828 Hom.: 579581 Cov.: 70 AF XY: 0.918 AC XY: 624457 AN XY: 680092

Gnomad4 AFR exome AF: 0.698

Gnomad4 AMR exome AF: 0.941

Gnomad4 ASJ exome AF: 0.926

Gnomad4 EAS exome AF: 0.996

Gnomad4 SAS exome AF: 0.960

Gnomad4 FIN exome AF: 0.924

Gnomad4 NFE exome AF: 0.915

Gnomad4 OTH exome AF: 0.911

GnomAD4 genome AF: 0.865 AC: 131647 AN: 152238 Hom.: 57704 Cov.: 35 AF XY: 0.869 AC XY: 64655 AN XY: 74438

Gnomad4 AFR AF: 0.709

Gnomad4 AMR AF: 0.913

Gnomad4 ASJ AF: 0.922

Gnomad4 EAS AF: 0.997

Gnomad4 SAS AF: 0.958

Gnomad4 FIN AF: 0.928

Gnomad4 NFE AF: 0.918

Gnomad4 OTH AF: 0.880

Alfa AF: 0.898 Hom.: 16800

Bravo AF: 0.855

Asia WGS AF: 0.963 AC: 3346 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	12
Dann	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs11136254; hg19: chr8-145158503; COSMIC: COSV59363023; COSMIC: COSV59363023;