NM_014614.3:c.5265G>C

Variant names:

• chr2-53866879-C-G
• NM_014614.3:c.5265G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014614.3(PSME4):​c.5265G>C​(p.Glu1755Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSME4 NM_014614.3 missense, splice_region
• Scores: Splicing: ADA: 0.00009231
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.914
• Publications: 0 publications found

Genes affected

PSME4 (HGNC:20635): (proteasome activator subunit 4) Predicted to enable lysine-acetylated histone binding activity; peptidase activator activity; and proteasome binding activity. Predicted to be involved in DNA repair; proteasomal ubiquitin-independent protein catabolic process; and spermatogenesis, exchange of chromosomal proteins. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03378275).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014614.3. 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
	PSME4	NM_014614.3	MANE Select	c.5265G>C	p.Glu1755Asp	missense splice_region	Exon 45 of 47	NP_055429.2	Q14997-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSME4	ENST00000404125.6	TSL:1 MANE Select	c.5265G>C	p.Glu1755Asp	missense splice_region	Exon 45 of 47	ENSP00000384211.1	Q14997-1
	PSME4	ENST00000389993.7	TSL:1	n.*3398G>C		splice_region non_coding_transcript_exon	Exon 44 of 46	ENSP00000374643.3	F8WBH5
	PSME4	ENST00000476586.5	TSL:1	n.438G>C		splice_region non_coding_transcript_exon	Exon 5 of 7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	14
DANN	Benign	0.92
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.4	N
PhyloP100		0.91
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.12
Sift	Benign	0.63	T
Sift4G	Benign	0.70	T
Polyphen		0.0	B
Vest4		0.060
MutPred		0.32		Loss of methylation at K1758 (P = 0.1018)
MVP		0.068
MPC		0.23
ClinPred		0.29	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.16
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000092
dbscSNV1_RF	Benign	0.0
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

hg19: chr2-54094016;