2-61188212-A-C

Variant names:

• chr2-61188212-A-C
• rs766433361
• NM_014709.4:c.10531T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014709.4(USP34):​c.10531T>G​(p.Phe3511Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. F3511L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: USP34 NM_014709.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.15
• Publications: 0 publications found

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]

AHSA2P (HGNC:):

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11297223).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014709.4. 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
	USP34	NM_014709.4	MANE Select	c.10531T>G	p.Phe3511Val	missense	Exon 80 of 80	NP_055524.3
	AHSA2P	NR_152210.1		n.2402A>C		non_coding_transcript_exon	Exon 6 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP34	ENST00000398571.7	TSL:5 MANE Select	c.10531T>G	p.Phe3511Val	missense	Exon 80 of 80	ENSP00000381577.2	Q70CQ2-1
	AHSA2P	ENST00000394457.7	TSL:1	n.3583A>C		non_coding_transcript_exon	Exon 6 of 6
	USP34	ENST00000411912.5	TSL:5	c.3559T>G	p.Phe1187Val	missense	Exon 26 of 26	ENSP00000398960.1	H7C183

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.0045
Eigen_PC	Benign	0.071
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.13
Sift	Benign	0.13	T
Sift4G	Benign	0.65	T
Polyphen		0.0	B
Vest4		0.25
MutPred		0.21		Gain of disorder (P = 0.1267)
MVP		0.068
ClinPred		0.25	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.073
gMVP		0.20
Mutation Taster		=85/15	polymorphism

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: rs766433361; hg19: chr2-61415347;