1-55077293-A-T

Variant names:

• chr1-55077293-A-T
• NM_015306.3:c.7322T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015306.3(USP24):​c.7322T>A​(p.Leu2441Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: USP24 NM_015306.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.39
• Publications: 0 publications found

Genes affected

USP24 (HGNC:12623): (ubiquitin specific peptidase 24) Modification of cellular proteins by ubiquitin is an essential regulatory mechanism controlled by the coordinated action of multiple ubiquitin-conjugating and deubiquitinating enzymes. USP24 belongs to a large family of cysteine proteases that function as deubiquitinating enzymes (Quesada et al., 2004 [PubMed 14715245]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015306.3. 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
	USP24	NM_015306.3	MANE Select	c.7322T>A	p.Leu2441Gln	missense	Exon 62 of 68	NP_056121.2	Q9UPU5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP24	ENST00000294383.7	TSL:5 MANE Select	c.7322T>A	p.Leu2441Gln	missense	Exon 62 of 68	ENSP00000294383.5	Q9UPU5
	USP24	ENST00000927917.1		c.7319T>A	p.Leu2440Gln	missense	Exon 62 of 68	ENSP00000597976.1
	USP24	ENST00000484447.6	TSL:3	c.7322T>A	p.Leu2441Gln	missense	Exon 62 of 68	ENSP00000489026.2	A0A0U1RQI9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000142 AC: 2 AN: 1407914 Hom.: 0 Cov.: 30 AF XY: 0.00000144 AC XY: 1 AN XY: 695880

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32402

American (AMR) AF: 0.00 AC: 0 AN: 38410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25092

East Asian (EAS) AF: 0.00 AC: 0 AN: 37790

South Asian (SAS) AF: 0.00 AC: 0 AN: 79316

European-Finnish (FIN) AF: 0.0000400 AC: 2 AN: 49996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081074

Other (OTH) AF: 0.00 AC: 0 AN: 58158

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.1	L
PhyloP100		8.4
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0020	D
Vest4		0.95
MVP		0.64
MPC		1.0
ClinPred		0.98	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.65
Mutation Taster		=62/38	polymorphism

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

hg19: chr1-55542966;