2-53866879-C-G

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -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. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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

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

Verdict is Likely_benign. Variant got -2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSME4	NM_014614.3	c.5265G>C	p.Glu1755Asp	missense_variant, splice_region_variant	Exon 45 of 47	ENST00000404125.6	NP_055429.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSME4	ENST00000404125.6	c.5265G>C	p.Glu1755Asp	missense_variant, splice_region_variant	Exon 45 of 47	1	NM_014614.3	ENSP00000384211.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5265G>C (p.E1755D) alteration is located in exon 45 (coding exon 45) of the PSME4 gene. This alteration results from a G to C substitution at nucleotide position 5265, causing the glutamic acid (E) at amino acid position 1755 to be replaced by an aspartic acid (D). 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	0.063
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
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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-54094016;