13-28662473-G-A

Position:

• chr13-28662473-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015932.6(POMP):​c.67G>A​(p.Gly23Arg) variant causes a missense change. 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: POMP NM_015932.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.39

Genes affected

POMP (HGNC:20330): (proteasome maturation protein) The protein encoded by this gene is a molecular chaperone that binds 20S preproteasome components and is essential for 20S proteasome formation. The 20S proteasome is the proteolytically active component of the 26S proteasome complex. The encoded protein is degraded before the maturation of the 20S proteasome is complete. A variant in the 5' UTR of this gene has been associated with KLICK syndrome, a rare skin disorder.[provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.787

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POMP	NM_015932.6	c.67G>A	p.Gly23Arg	missense_variant	2/6	ENST00000380842.5	NP_057016.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POMP	ENST00000380842.5	c.67G>A	p.Gly23Arg	missense_variant	2/6	1	NM_015932.6	ENSP00000370222.4

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 provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 24, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 23 of the POMP protein (p.Gly23Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with POMP-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.52
Sift	Benign	0.048	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.21	B
Vest4		0.66
MutPred		0.75		Gain of catalytic residue at L19 (P = 0.0077);
MVP		0.17
MPC		0.73
ClinPred		0.96	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr13-29236610; COSMIC: COSV66481239;