chr8-144099585-G-C

Variant names:

• chr8-144099585-G-C
• rs761738333
• NM_030974.4:c.693C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_030974.4(SHARPIN):​c.693C>G​(p.Ala231Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A231A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SHARPIN NM_030974.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00100
• Publications: 0 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: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP7: Synonymous conserved (PhyloP=0.001 with no splicing effect.

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.693C>G	p.Ala231Ala	synonymous	Exon 5 of 9	NP_112236.3
	SHARPIN	NR_038270.2		n.713C>G		non_coding_transcript_exon	Exon 5 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHARPIN	ENST00000398712.7	TSL:1 MANE Select	c.693C>G	p.Ala231Ala	synonymous	Exon 5 of 9	ENSP00000381698.2	Q9H0F6-1
	SHARPIN	ENST00000359551.6	TSL:1	n.693C>G		non_coding_transcript_exon	Exon 5 of 8	ENSP00000352551.6	Q9H0F6-2
	SHARPIN	ENST00000964196.1		c.699C>G	p.Ala233Ala	synonymous	Exon 5 of 9	ENSP00000634255.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248844 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.83
DANN	Benign	0.55
PhyloP100		0.0010
PromoterAI		-0.0078	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs761738333; hg19: chr8-145154488;