NM_030974.4:c.201+10G>A

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
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• autoinflammation with episodic fever and immune dysregulation

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030974.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHARPIN	NM_030974.4	MANE Select	c.201+10G>A		intron	N/A	NP_112236.3
	SHARPIN	NR_038270.2		n.221+10G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHARPIN	ENST00000398712.7	TSL:1 MANE Select	c.201+10G>A		intron	N/A	ENSP00000381698.2
	SHARPIN	ENST00000359551.6	TSL:1	n.201+10G>A		intron	N/A	ENSP00000352551.6
	SHARPIN	ENST00000531375.1	TSL:2	n.204+10G>A		intron	N/A

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

African (AFR) AF: 0.698 AC: 21774 AN: 31202

American (AMR) AF: 0.941 AC: 33419 AN: 35506

Ashkenazi Jewish (ASJ) AF: 0.926 AC: 23209 AN: 25058

East Asian (EAS) AF: 0.996 AC: 35381 AN: 35520

South Asian (SAS) AF: 0.960 AC: 75819 AN: 78988

European-Finnish (FIN) AF: 0.924 AC: 30877 AN: 33402

Middle Eastern (MID) AF: 0.903 AC: 3827 AN: 4236

European-Non Finnish (NFE) AF: 0.915 AC: 986190 AN: 1077358

Other (OTH) 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

African (AFR) AF: 0.710 AC: 29475 AN: 41540

American (AMR) AF: 0.913 AC: 13973 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.922 AC: 3201 AN: 3472

East Asian (EAS) AF: 0.997 AC: 5163 AN: 5178

South Asian (SAS) AF: 0.958 AC: 4632 AN: 4834

European-Finnish (FIN) AF: 0.928 AC: 9836 AN: 10602

Middle Eastern (MID) AF: 0.880 AC: 257 AN: 292

European-Non Finnish (NFE) AF: 0.918 AC: 62417 AN: 68008

Other (OTH) AF: 0.879 AC: 1857 AN: 2112

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	7.8
DANN	Benign	0.77
PhyloP100		-0.17
PromoterAI		-0.029	Neutral
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

Other links and lift over

dbSNP: rs12549149; hg19: chr8-145158446;