13-75566726-A-T

Variant names:

• chr13-75566726-A-T
• rs1198272356
• NM_006002.5:c.215A>T

Variant summary

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

The NM_006002.5(UCHL3):​c.215A>T​(p.Lys72Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K72R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: UCHL3 NM_006002.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.25
• Publications: 0 publications found

Genes affected

UCHL3 (HGNC:12515): (ubiquitin C-terminal hydrolase L3) The protein encoded by this gene is a member of the deubiquitinating enzyme family. Members of this family are proteases that catalyze the removal of ubiquitin from polypeptides and are divided into five classes, depending on the mechanism of catalysis. This protein may hydrolyze the ubiquitinyl-N-epsilon amide bond of ubiquitinated proteins to regenerate ubiquitin for another catalytic cycle. Alternative splicing results in multiple transcript variants that encode different protein isoforms. [provided by RefSeq, Aug 2012]

ENSG00000261553 (HGNC:):

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=0.3090052).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006002.5. 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
	UCHL3	NM_006002.5	MANE Select	c.215A>T	p.Lys72Ile	missense	Exon 4 of 9	NP_005993.1	A0A140VJZ4
	UCHL3	NM_001270952.2		c.107A>T	p.Lys36Ile	missense	Exon 4 of 9	NP_001257881.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UCHL3	ENST00000377595.8	TSL:1 MANE Select	c.215A>T	p.Lys72Ile	missense	Exon 4 of 9	ENSP00000366819.3	P15374
	UCHL3	ENST00000963592.1		c.215A>T	p.Lys72Ile	missense	Exon 4 of 10	ENSP00000633651.1
	UCHL3	ENST00000963593.1		c.215A>T	p.Lys72Ile	missense	Exon 4 of 10	ENSP00000633652.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000414 AC: 1 AN: 241486 AF XY: 0.00000765

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000313

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448232 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 720392

⚠️ 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: 32804

American (AMR) AF: 0.0000235 AC: 1 AN: 42532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25780

East Asian (EAS) AF: 0.00 AC: 0 AN: 39142

South Asian (SAS) AF: 0.00 AC: 0 AN: 83762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52660

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106058

Other (OTH) AF: 0.00 AC: 0 AN: 59766

⚠️ 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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.084
Eigen_PC	Benign	0.074
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.11
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.034	D
Polyphen		0.063	B
Vest4		0.26
MutPred		0.42		Loss of ubiquitination at K72 (P = 0.0019)
MVP		0.69
MPC		0.74
ClinPred		0.92	D
GERP RS		4.6
PromoterAI		-0.034	Neutral
Varity_R		0.66
gMVP		0.52
Mutation Taster		=50/50

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

dbSNP: rs1198272356; hg19: chr13-76140862;