13-28662489-A-C

Position:

chr13-28662489-A-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_015932.6(POMP):c.83A>C(p.His28Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00083 in 1,612,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00088 ( 0 hom. )

Consequence

POMP
NM_015932.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 4.71

Variant links:

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]

POMP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.104105085).

BS2

High AC in GnomAd4 at 56 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POMP	NM_015932.6 linkuse as main transcript	c.83A>C	p.His28Pro	missense_variant	2/6	ENST00000380842.5	NP_057016.1	Q9Y244

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POMP	ENST00000380842.5 linkuse as main transcript	c.83A>C	p.His28Pro	missense_variant	2/6	1	NM_015932.6	ENSP00000370222.4		Q9Y244

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000720

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000294

AC:

AN:

251436

Hom.:

AF XY:

0.000280

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000572

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000878

AC:

1282

AN:

1460212

Hom.:

Cov.:

AF XY:

0.000847

AC XY:

615

AN XY:

726458

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.00110

Gnomad4 OTH exome

AF:

0.000712

GnomAD4 genome

AF:

0.000368

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000720

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000612

Hom.:

Bravo

AF:

0.000393

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000272

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 28 of the POMP protein (p.His28Pro). This variant is present in population databases (rs140397494, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with POMP-related conditions. ClinVar contains an entry for this variant (Variation ID: 1449348). 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. -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

POMP-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 09, 2024

The POMP c.83A>C variant is predicted to result in the amino acid substitution p.His28Pro. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.058% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is likely too common for an undocumented disease-causing variant. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2024

The c.83A>C (p.H28P) alteration is located in exon 2 (coding exon 2) of the POMP gene. This alteration results from a A to C substitution at nucleotide position 83, causing the histidine (H) at amino acid position 28 to be replaced by a proline (P). 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

Benign

0.076

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.082

Eigen

Benign

-0.038

Eigen_PC

Benign

0.18

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.66

M_CAP

Benign

0.0027

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.2

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.6

REVEL

Benign

0.19

Sift

Benign

0.31

Sift4G

Benign

0.27

Polyphen

0.0

Vest4

0.51

MVP

0.35

MPC

0.57

ClinPred

0.040

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.28

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over