chr18-26134044-G-A

Position:

• chr18-26134044-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000415576.7(PSMA8):​c.79G>A​(p.Ala27Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PSMA8 ENST00000415576.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.05

Genes affected

PSMA8 (HGNC:22985): (proteasome 20S subunit alpha 8) Predicted to be involved in meiotic cell cycle and proteasomal protein catabolic process. Located in extracellular exosome and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMA8	NM_001025096.2	c.79G>A	p.Ala27Thr	missense_variant	1/7	ENST00000415576.7	NP_001020267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMA8	ENST00000415576.7	c.79G>A	p.Ala27Thr	missense_variant	1/7	1	NM_001025096.2	ENSP00000409284	P3
PSMA8	ENST00000308268.10	c.79G>A	p.Ala27Thr	missense_variant	1/7	1		ENSP00000311121	A1
PSMA8	ENST00000343848.10	c.79G>A	p.Ala27Thr	missense_variant	1/7	1		ENSP00000345584
PSMA8	ENST00000538664.2	c.79G>A	p.Ala27Thr	missense_variant, NMD_transcript_variant	1/8	1		ENSP00000440327

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

The c.79G>A (p.A27T) alteration is located in exon 1 (coding exon 1) of the PSMA8 gene. This alteration results from a G to A substitution at nucleotide position 79, causing the alanine (A) at amino acid position 27 to be replaced by a threonine (T). 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	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.46	.;.;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	-0.12	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.81	P;P;P
Vest4		0.81
MutPred		0.85		Gain of ubiquitination at K29 (P = 0.07);Gain of ubiquitination at K29 (P = 0.07);Gain of ubiquitination at K29 (P = 0.07);
MVP		0.77
MPC		0.16
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.53
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr18-23714008;