chr8-144099283-C-G

Variant names:

• chr8-144099283-C-G
• rs562533242
• NM_030974.4:c.916G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030974.4(SHARPIN):​c.916G>C​(p.Ala306Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SHARPIN NM_030974.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.06

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08009437).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHARPIN	NM_030974.4	c.916G>C	p.Ala306Pro	missense_variant	Exon 6 of 9	ENST00000398712.7	NP_112236.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHARPIN	ENST00000398712.7	c.916G>C	p.Ala306Pro	missense_variant	Exon 6 of 9	1	NM_030974.4	ENSP00000381698.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461802 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.015	T;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.51	T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.080	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	.;M
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.042
Sift	Benign	0.32	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.0010	.;B
Vest4		0.23
MutPred		0.26		.;Gain of catalytic residue at A306 (P = 0.0029);
MVP		0.39
MPC		0.21
ClinPred		0.22	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.26
gMVP		0.48

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: rs562533242; hg19: chr8-145154186;