NM_014614.3:c.4022G>A

Variant names:

• chr2-53893690-C-T
• rs201669390
• NM_014614.3:c.4022G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_014614.3(PSME4):​c.4022G>A​(p.Arg1341His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 1,609,624 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1341C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: PSME4 NM_014614.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79
• Publications: 4 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 -4 ACMG points.

• BS2: High AC in GnomAd4 at 27 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.4022G>A	p.Arg1341His	missense	Exon 35 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.4022G>A	p.Arg1341His	missense	Exon 35 of 47	ENSP00000384211.1	Q14997-1
	PSME4	ENST00000389993.7	TSL:1	n.*2155G>A		non_coding_transcript_exon	Exon 34 of 46	ENSP00000374643.3	F8WBH5
	PSME4	ENST00000389993.7	TSL:1	n.*2155G>A		3_prime_UTR	Exon 34 of 46	ENSP00000374643.3	F8WBH5

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 152058 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000324

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000189 AC: 47 AN: 249006 AF XY: 0.000193

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000390

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000301 AC: 438 AN: 1457566 Hom.: 0 Cov.: 32 AF XY: 0.000273 AC XY: 198 AN XY: 724992

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000901 AC: 3 AN: 33310

American (AMR) AF: 0.0000226 AC: 1 AN: 44306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25988

East Asian (EAS) AF: 0.00 AC: 0 AN: 39404

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85608

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.000359 AC: 398 AN: 1109840

Other (OTH) AF: 0.000549 AC: 33 AN: 60122

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000178 AC: 27 AN: 152058 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74244

African (AFR) AF: 0.000121 AC: 5 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

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

European-Non Finnish (NFE) AF: 0.000324 AC: 22 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000212 Hom.: 0

Bravo AF: 0.000162

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000255 AC: 31

EpiCase AF: 0.000273

EpiControl AF: 0.000415

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	0.29
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		7.8
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.82
MVP		0.30
MPC		0.48
ClinPred		0.33	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.68
Mutation Taster		=41/59	disease causing

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: rs201669390; hg19: chr2-54120827;