rs11136254

Variant names:

• chr8-144103600-G-T
• rs11136254
• NM_030974.4:c.154C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_030974.4(SHARPIN):​c.154C>A​(p.Arg52Arg) 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.788
• Publications: 19 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]

MAF1 (HGNC:24966): (MAF1 homolog, negative regulator of RNA polymerase III) This gene encodes a protein that is similar to Maf1, a Saccharomyces cerevisiae protein highly conserved in eukaryotic cells. Yeast Maf1 is a negative effector of RNA polymerase III (Pol III). It responds to changes in the cellular environment and represses pol III transcription. Biochemical studies identified the initiation factor TFIIIB as a target for Maf1-dependent repression. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -21 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 VariationId is 403434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHARPIN	NM_030974.4	MANE Select	c.154C>A	p.Arg52Arg	synonymous	Exon 1 of 9	NP_112236.3
	SHARPIN	NR_038270.2		n.174C>A		non_coding_transcript_exon	Exon 1 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHARPIN	ENST00000398712.7	TSL:1 MANE Select	c.154C>A	p.Arg52Arg	synonymous	Exon 1 of 9	ENSP00000381698.2	Q9H0F6-1
	SHARPIN	ENST00000359551.6	TSL:1	n.154C>A		non_coding_transcript_exon	Exon 1 of 8	ENSP00000352551.6	Q9H0F6-2
	SHARPIN	ENST00000964196.1		c.154C>A	p.Arg52Arg	synonymous	Exon 1 of 9	ENSP00000634255.1

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

GnomAD2 exomes AF: 0.927 AC: 117876 AN: 127126 AF XY: 0.930

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 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

African (AFR) AF: 0.698 AC: 21717 AN: 31106

American (AMR) AF: 0.941 AC: 33538 AN: 35628

Ashkenazi Jewish (ASJ) AF: 0.926 AC: 23206 AN: 25054

East Asian (EAS) AF: 0.996 AC: 35422 AN: 35562

South Asian (SAS) AF: 0.960 AC: 75873 AN: 79038

European-Finnish (FIN) AF: 0.924 AC: 30902 AN: 33430

Middle Eastern (MID) AF: 0.904 AC: 3807 AN: 4210

European-Non Finnish (NFE) AF: 0.915 AC: 986068 AN: 1077246

Other (OTH) AF: 0.911 AC: 52449 AN: 57554

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

African (AFR) AF: 0.709 AC: 29453 AN: 41520

American (AMR) AF: 0.913 AC: 13966 AN: 15304

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

East Asian (EAS) AF: 0.997 AC: 5159 AN: 5174

South Asian (SAS) AF: 0.958 AC: 4630 AN: 4832

European-Finnish (FIN) AF: 0.928 AC: 9848 AN: 10612

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

European-Non Finnish (NFE) AF: 0.918 AC: 62415 AN: 68008

Other (OTH) AF: 0.880 AC: 1859 AN: 2112

Alfa AF: 0.891 Hom.: 18391

Bravo AF: 0.855

Asia WGS AF: 0.963 AC: 3346 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	12
DANN	Benign	0.88
PhyloP100		0.79
PromoterAI		0.042	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)		0.0		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: rs11136254; hg19: chr8-145158503; COSMIC: COSV59363023; COSMIC: COSV59363023;