chr8-144098924-G-A

Position:

• chr8-144098924-G-A

Variant summary

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

The NM_030974.4(SHARPIN):​c.1118C>T​(p.Thr373Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,442,638 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SHARPIN NM_030974.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHARPIN	NM_030974.4	c.1118C>T	p.Thr373Ile	missense_variant	8/9	ENST00000398712.7	NP_112236.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHARPIN	ENST00000398712.7	c.1118C>T	p.Thr373Ile	missense_variant	8/9	1	NM_030974.4	ENSP00000381698	P1
SHARPIN	ENST00000359551.6	c.*12C>T		3_prime_UTR_variant, NMD_transcript_variant	7/8	1		ENSP00000352551
SHARPIN	ENST00000532536.5	c.242C>T	p.Thr81Ile	missense_variant	3/3	3		ENSP00000432355

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1442638 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 717830

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: 0.0000240

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2024

The c.1118C>T (p.T373I) alteration is located in exon 8 (coding exon 8) of the SHARPIN gene. This alteration results from a C to T substitution at nucleotide position 1118, causing the threonine (T) at amino acid position 373 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.5	.;M
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Uncertain	0.37
Sift	Benign	0.047	D;D
Sift4G	Uncertain	0.050	T;D
Polyphen		1.0	.;D
Vest4		0.55
MutPred		0.40		.;Loss of phosphorylation at T373 (P = 0.0323);
MVP		0.76
MPC		0.69
ClinPred		0.98	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.68

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-145153827; COSMIC: COSV59645227; COSMIC: COSV59645227;