Genetic Variant PAAF1:p.Lys117Arg (chr11-73899213-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_025155.3(PAAF1):c.350A>G(p.Lys117Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

PAAF1
NM_025155.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.42

Publications

0 publications found

Variant links:

Genes affected

PAAF1 (HGNC:25687): (proteasomal ATPase associated factor 1) This gene encodes a WD repeat-containing protein involved in regulation of association of proteasome components. During HIV infection, the encoded protein is thought to promote provirus transcription through recruitment of the 19S regulatory complex. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jun 2012]

PAAF1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAAF1	NM_025155.3 link	c.350A>G	p.Lys117Arg	missense_variant	Exon 5 of 12	ENST00000310571.8	NP_079431.1	Q9BRP4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAAF1	ENST00000310571.8 link	c.350A>G	p.Lys117Arg	missense_variant	Exon 5 of 12	1	NM_025155.3	ENSP00000311665.4		Q9BRP4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461832

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111974

Other (OTH)

AF:

0.00

AC:

AN:

60394

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 25, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.350A>G (p.K117R) alteration is located in exon 5 (coding exon 5) of the PAAF1 gene. This alteration results from a A to G substitution at nucleotide position 350, causing the lysine (K) at amino acid position 117 to be replaced by an arginine (R). 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

0.093

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0037

.;T;T;T;.;.;.;.;.;T;.

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

.;D;D;D;T;T;.;.;D;D;D

M_CAP

Benign

0.018

MetaRNN

Uncertain

0.63

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.17

MutationAssessor

Benign

1.4

.;L;.;.;.;.;.;.;.;.;.

PhyloP100

6.4

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.56

N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.22

Sift

Benign

0.38

T;T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.40

T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.21, 1.0

.;B;.;.;.;.;D;D;D;.;.

Vest4

0.55

MutPred

0.63

.;Loss of ubiquitination at K117 (P = 0.0161);.;.;.;.;.;.;.;.;.;

MVP

0.84

MPC

0.83

ClinPred

0.92

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.41

Mutation Taster

=77/23

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over