Genetic Variant NM_015932.6:c.50C>A (chr13-28662456-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015932.6(POMP):c.50C>A(p.Thr17Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T17I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

POMP
NM_015932.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.31

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

proteasome-associated autoinflammatory syndrome 2
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
keratosis linearis-ichthyosis congenita-sclerosing keratoderma syndrome
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

POMP links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.124761194).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015932.6. 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
	POMP	NM_015932.6	MANE Select	c.50C>A	p.Thr17Asn	missense	Exon 2 of 6	NP_057016.1	Q9Y244

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POMP	ENST00000380842.5	TSL:1 MANE Select	c.50C>A	p.Thr17Asn	missense	Exon 2 of 6	ENSP00000370222.4	Q9Y244
POMP	ENST00000460403.1	TSL:3	c.-134C>A		5_prime_UTR_premature_start_codon_gain	Exon 3 of 7	ENSP00000492579.1	A0A1W2PS02
POMP	ENST00000697661.1		c.-134C>A		5_prime_UTR_premature_start_codon_gain	Exon 3 of 7	ENSP00000513386.1	A0A1W2PS02

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461660

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111846

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.033

Eigen

Benign

0.021

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.84

M_CAP

Benign

0.0029

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.7

PhyloP100

2.3

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.36

REVEL

Benign

0.12

Sift

Benign

0.044

Sift4G

Benign

0.30

Polyphen

0.12

Vest4

0.18

MutPred

0.44

Gain of catalytic residue at L19 (P = 0.0017)

MVP

0.32

MPC

0.42

ClinPred

0.52

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.16

gMVP

0.48

Mutation Taster

=88/12

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over