NM_014614.3:c.4188A>T

Variant names:

• chr2-53892811-T-A
• rs747915522
• NM_014614.3:c.4188A>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_014614.3(PSME4):​c.4188A>T​(p.Glu1396Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,609,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: PSME4 NM_014614.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0360
• Publications: 1 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03104189).
• BS2: High AC in GnomAd4 at 18 AD gene.

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.4188A>T	p.Glu1396Asp	missense	Exon 36 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.4188A>T	p.Glu1396Asp	missense	Exon 36 of 47	ENSP00000384211.1	Q14997-1
	PSME4	ENST00000389993.7	TSL:1	n.*2321A>T		non_coding_transcript_exon	Exon 35 of 46	ENSP00000374643.3	F8WBH5
	PSME4	ENST00000389993.7	TSL:1	n.*2321A>T		3_prime_UTR	Exon 35 of 46	ENSP00000374643.3	F8WBH5

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000101 AC: 25 AN: 246512 AF XY: 0.0000976

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000196

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000202 AC: 295 AN: 1457580 Hom.: 0 Cov.: 30 AF XY: 0.000203 AC XY: 147 AN XY: 724930

African (AFR) AF: 0.00 AC: 0 AN: 33316

American (AMR) AF: 0.00 AC: 0 AN: 43760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25896

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 85150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.000264 AC: 293 AN: 1110554

Other (OTH) AF: 0.0000332 AC: 2 AN: 60204

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74338

African (AFR) AF: 0.0000724 AC: 3 AN: 41442

American (AMR) AF: 0.0000655 AC: 1 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000168 Hom.: 0

Bravo AF: 0.000136

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.000164

EpiControl AF: 0.000178

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	0.088
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.061	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.55
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.65	N
PhyloP100		-0.036
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.074
Sift	Benign	0.89	T
Sift4G	Benign	0.60	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.35		Loss of methylation at K1397 (P = 0.0814)
MVP		0.082
MPC		0.24
ClinPred		0.075	T
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.067
gMVP		0.12
Mutation Taster		=72/28	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: rs747915522; hg19: chr2-54119948;