chr1-55077300-T-C

Variant names:

• chr1-55077300-T-C
• NM_015306.3:c.7315A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015306.3(USP24):​c.7315A>G​(p.Asn2439Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,402,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: USP24 NM_015306.3 missense, splice_region
• Scores: Splicing: ADA: 0.5561
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.20
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30656442).

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.7315A>G	p.Asn2439Asp	missense splice_region	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.7315A>G	p.Asn2439Asp	missense splice_region	Exon 62 of 68	ENSP00000294383.5	Q9UPU5
	USP24	ENST00000927917.1		c.7312A>G	p.Asn2438Asp	missense splice_region	Exon 62 of 68	ENSP00000597976.1
	USP24	ENST00000484447.6	TSL:3	c.7315A>G	p.Asn2439Asp	missense splice_region	Exon 62 of 68	ENSP00000489026.2	A0A0U1RQI9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1402598 Hom.: 0 Cov.: 30 AF XY: 0.00000144 AC XY: 1 AN XY: 692806

⚠️ 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: 32136

American (AMR) AF: 0.00 AC: 0 AN: 37576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24996

East Asian (EAS) AF: 0.00 AC: 0 AN: 37502

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49736

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078388

Other (OTH) AF: 0.00 AC: 0 AN: 57992

⚠️ 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.: 32

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	Benign	0.24
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.040	T
Eigen	Benign	0.025
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.0	N
PhyloP100		7.2
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.14
Sift	Benign	0.42	T
Sift4G	Uncertain	0.052	T
Vest4		0.28
MVP		0.10
MPC		0.52
ClinPred		0.79	D
GERP RS		5.9
Varity_R		0.20
gMVP		0.30
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.56
dbscSNV1_RF	Benign	0.42
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: chr1-55542973;