18-26178921-T-C

Position:

• chr18-26178921-T-C

Variant summary

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

The NM_001025096.2(PSMA8):​c.569T>C​(p.Ile190Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,130 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PSMA8 NM_001025096.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.57

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, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMA8	NM_001025096.2	c.569T>C	p.Ile190Thr	missense_variant	5/7	ENST00000415576.7	NP_001020267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMA8	ENST00000415576.7	c.569T>C	p.Ile190Thr	missense_variant	5/7	1	NM_001025096.2	ENSP00000409284.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461130 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726818

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

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

Sep 14, 2022

The c.587T>C (p.I196T) alteration is located in exon 5 (coding exon 5) of the PSMA8 gene. This alteration results from a T to C substitution at nucleotide position 587, causing the isoleucine (I) at amino acid position 196 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	Uncertain	0.46
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	.;.;T;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Benign	-0.93	T
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.4	D;D;D;.
REVEL	Uncertain	0.32
Sift	Benign	0.042	D;D;D;.
Sift4G	Uncertain	0.056	T;D;D;T
Polyphen		0.026	B;B;B;.
Vest4		0.80
MutPred		0.81		.;.;Loss of stability (P = 0.0145);.;
MVP		0.42
MPC		0.35
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.37
gMVP		0.71

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-23758885;