Genetic Variant NM_014709.4:c.10565C>T (chr2-61188178-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014709.4(USP34):c.10565C>T(p.Thr3522Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

USP34
NM_014709.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.50

Variant links:

Genes affected

USP34 (HGNC:20066): (ubiquitin specific peptidase 34) Enables cysteine-type endopeptidase activity and thiol-dependent deubiquitinase. Involved in positive regulation of canonical Wnt signaling pathway and protein K48-linked deubiquitination. Predicted to be active in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

USP34 links:

AHSA2P (HGNC:20437): (activator of HSP90 ATPase homolog 2, pseudogene) Predicted to enable ATPase activator activity. Predicted to be involved in positive regulation of ATPase activity and protein folding. Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

AHSA2P links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13382131).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP34	NM_014709.4 link	c.10565C>T	p.Thr3522Ile	missense_variant	Exon 80 of 80	ENST00000398571.7	NP_055524.3	Q70CQ2-1
AHSA2P	NR_152210.1 link	n.2368G>A		non_coding_transcript_exon_variant	Exon 6 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
USP34	ENST00000398571.7 link	c.10565C>T	p.Thr3522Ile	missense_variant	Exon 80 of 80	5	NM_014709.4	ENSP00000381577.2	Q70CQ2-1
AHSA2P	ENST00000394457.7 link	n.3549G>A		non_coding_transcript_exon_variant	Exon 6 of 6	1
USP34	ENST00000411912.5 link	c.3593C>T	p.Thr1198Ile	missense_variant	Exon 26 of 26	5		ENSP00000398960.1	H7C183
USP34	ENST00000436269.1 link	c.1199C>T	p.Thr400Ile	missense_variant	Exon 7 of 7	5		ENSP00000398489.1	H7C150

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249066

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135140

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

6.84e-7

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.10565C>T (p.T3522I) alteration is located in exon 80 (coding exon 80) of the USP34 gene. This alteration results from a C to T substitution at nucleotide position 10565, causing the threonine (T) at amino acid position 3522 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

Benign

0.16

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.045

T;T

Eigen

Benign

-0.085

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.0047

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.20

N;.

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.073

Sift

Benign

0.21

T;T

Sift4G

Uncertain

0.027

D;D

Polyphen

0.0

B;.

Vest4

0.19

MutPred

0.30

Loss of phosphorylation at T3522 (P = 0.0766);.;

MVP

0.043

ClinPred

0.36

GERP RS

5.5

Varity_R

0.12

gMVP

0.39

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