Genetic Variant USP22:p.Gln43His (chr17-21042707-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_015276.2(USP22):c.129G>C(p.Gln43His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000778 in 1,286,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.8e-7 ( 0 hom. )

Consequence

USP22
NM_015276.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.55

Variant links:

Genes affected

USP22 (HGNC:12621): (ubiquitin specific peptidase 22) Enables enzyme binding activity; nuclear receptor coactivator activity; and thiol-dependent deubiquitinase. Contributes to H4 histone acetyltransferase activity. Involved in positive regulation of mitotic cell cycle; positive regulation of transcription, DNA-templated; and protein modification by small protein conjugation or removal. Part of SAGA complex. [provided by Alliance of Genome Resources, Apr 2022]

USP22 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3827191).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP22	NM_015276.2 link	c.129G>C	p.Gln43His	missense_variant	Exon 1 of 13	ENST00000261497.9	NP_056091.1	Q9UPT9-1
USP22	XM_047435703.1 link	c.-54G>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 12		XP_047291659.1
USP22	XM_047435703.1 link	c.-54G>C		5_prime_UTR_variant	Exon 1 of 12		XP_047291659.1
USP22	XM_005256575.3 link	c.-145+614G>C		intron_variant	Intron 1 of 12		XP_005256632.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP22	ENST00000261497.9 link	c.129G>C	p.Gln43His	missense_variant	Exon 1 of 13	1	NM_015276.2	ENSP00000261497.4		Q9UPT9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.78e-7

AC:

AN:

1286138

Hom.:

Cov.:

AF XY:

0.00000158

AC XY:

AN XY:

631230

show subpopulations

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:

9.81e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.129G>C (p.Q43H) alteration is located in exon 1 (coding exon 1) of the USP22 gene. This alteration results from a G to C substitution at nucleotide position 129, causing the glutamine (Q) at amino acid position 43 to be replaced by a histidine (H). 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

Benign

0.21

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.058

Eigen

Benign

0.17

Eigen_PC

Benign

0.14

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.83

M_CAP

Benign

0.063

MetaRNN

Benign

0.38

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.8

REVEL

Benign

0.12

Sift

Benign

0.51

Sift4G

Benign

0.19

Polyphen

0.89

Vest4

0.53

MutPred

0.56

Gain of sheet (P = 0.0477);

MVP

0.40

MPC

0.84

ClinPred

0.71

GERP RS

2.5

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.16

gMVP

0.61

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over