Genetic Variant NM_014709.4:c.10364G>C (chr2-61188379-C-G) – 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.10364G>C(p.Cys3455Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,918 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 2 hom. )

Consequence

USP34
NM_014709.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.42

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=0.021837682).

BS2

High AC in GnomAdExome4 at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP34	NM_014709.4 link	c.10364G>C	p.Cys3455Ser	missense_variant	Exon 80 of 80	ENST00000398571.7	NP_055524.3	Q70CQ2-1
AHSA2P	NR_152210.1 link	n.2569C>G		non_coding_transcript_exon_variant	Exon 6 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP34	ENST00000398571.7 link	c.10364G>C	p.Cys3455Ser	missense_variant	Exon 80 of 80	5	NM_014709.4	ENSP00000381577.2		Q70CQ2-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000281

AC:

AN:

249536

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135380

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000278

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1461720

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000579

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.10364G>C (p.C3455S) alteration is located in exon 80 (coding exon 80) of the USP34 gene. This alteration results from a G to C substitution at nucleotide position 10364, causing the cysteine (C) at amino acid position 3455 to be replaced by a serine (S). 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

0.069

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.019

T;T

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.49

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.65

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.022

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.20

N;.

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.81

N;N

REVEL

Benign

0.062

Sift

Benign

0.49

T;T

Sift4G

Benign

0.73

T;T

Polyphen

0.0

B;.

Vest4

0.18

MutPred

0.16

Gain of phosphorylation at C3455 (P = 0.011);.;

MVP

0.043

ClinPred

0.016

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.085

gMVP

0.19

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