Genetic Variant PAAF1:p.Gln157His (chr11-73900359-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_025155.3(PAAF1):c.471G>C(p.Gln157His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000601 in 1,612,774 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000043 ( 1 hom. )

Consequence

PAAF1
NM_025155.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.52

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08550915).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAAF1	NM_025155.3 link	c.471G>C	p.Gln157His	missense_variant	Exon 6 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.471G>C	p.Gln157His	missense_variant	Exon 6 of 12	1	NM_025155.3	ENSP00000311665.4		Q9BRP4-1

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000131

AC:

AN:

251034

AF XY:

0.000118

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000931

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000431

AC:

AN:

1460460

Hom.:

Cov.:

AF XY:

0.0000427

AC XY:

AN XY:

726628

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33462

American (AMR)

AF:

0.00132

AC:

AN:

44656

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86088

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111012

Other (OTH)

AF:

0.0000332

AC:

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000223

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41580

American (AMR)

AF:

0.00222

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2114

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

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.000283

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 30, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.471G>C (p.Q157H) alteration is located in exon 6 (coding exon 6) of the PAAF1 gene. This alteration results from a G to C substitution at nucleotide position 471, causing the glutamine (Q) at amino acid position 157 to be replaced by a histidine (H). 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

Pathogenic

0.62

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.078

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

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.84

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

M_CAP

Benign

0.011

MetaRNN

Benign

0.086

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

MetaSVM

Benign

-0.57

MutationAssessor

Benign

0.54

.;N;.;.;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.9

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

REVEL

Benign

0.23

Sift

Benign

0.035

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

Sift4G

Benign

0.36

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

Polyphen

0.60, 0.99

.;P;.;.;.;.;D;D;.;D;.;.

Vest4

0.74

MutPred

0.57

.;Loss of ubiquitination at K159 (P = 0.1435);.;.;.;.;.;.;.;.;.;.;

MVP

0.67

MPC

0.25

ClinPred

0.24

GERP RS

4.8

PromoterAI

-0.013

Neutral

(source)

Varity_R

0.30

gMVP

0.44

Mutation Taster

=86/14

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

LitVar

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

11-73900359-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over