Genetic Variant USP34:p.Val3534Ile (chr2-61188143-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_014709.4(USP34):c.10600G>A(p.Val3534Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,613,782 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 2 hom. )

Consequence

USP34
NM_014709.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.89

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05747345).

BS2

High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP34	NM_014709.4 link	c.10600G>A	p.Val3534Ile	missense_variant	Exon 80 of 80	ENST00000398571.7	NP_055524.3	Q70CQ2-1
AHSA2P	NR_152210.1 link	n.2333C>T		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.10600G>A	p.Val3534Ile	missense_variant	Exon 80 of 80	5	NM_014709.4	ENSP00000381577.2	Q70CQ2-1
AHSA2P	ENST00000394457.7 link	n.3514C>T		non_coding_transcript_exon_variant	Exon 6 of 6	1
USP34	ENST00000411912.5 link	c.3628G>A	p.Val1210Ile	missense_variant	Exon 26 of 26	5		ENSP00000398960.1	H7C183
USP34	ENST00000436269.1 link	c.1234G>A	p.Val412Ile	missense_variant	Exon 7 of 7	5		ENSP00000398489.1	H7C150

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000443

AC:

AN:

248148

Hom.:

AF XY:

0.0000371

AC XY:

AN XY:

134598

show subpopulations

Gnomad AFR exome

AF:

0.000518

Gnomad AMR exome

AF:

0.00

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:

0.0000267

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461556

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727050

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000929

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000131

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000458

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000986

Hom.:

Bravo

AF:

0.000140

ESP6500AA

AF:

0.000516

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000745

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.10600G>A (p.V3534I) alteration is located in exon 80 (coding exon 80) of the USP34 gene. This alteration results from a G to A substitution at nucleotide position 10600, causing the valine (V) at amino acid position 3534 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

0.089

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.028

T;T

Eigen

Benign

-0.16

Eigen_PC

Benign

0.030

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.0073

MetaRNN

Benign

0.057

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.20

N;.

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.23

N;N

REVEL

Benign

0.093

Sift

Benign

0.032

D;D

Sift4G

Benign

0.40

T;D

Polyphen

0.0030

B;.

Vest4

0.21

MVP

0.043

ClinPred

0.077

GERP RS

4.7

Varity_R

0.092

gMVP

0.37

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