Genetic Variant PABPC5:p.Glu5Lys (chrX-91435590-G-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_080832.3(PABPC5):c.13G>A(p.Glu5Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000665 in 1,202,337 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000064 ( 0 hom. 1 hem. )

Consequence

PABPC5
NM_080832.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.05

Publications

2 publications found

Variant links:

Genes affected

PABPC5 (HGNC:13629): (poly(A) binding protein cytoplasmic 5) This gene encodes a protein that binds to the polyA tail found at the 3' end of most eukaryotic mRNAs. It is thought to play a role in the regulation of mRNA metabolic processes in the cytoplasm. This gene is located in a gene-poor region within the X-specific 13d-sY43 subinterval of the chromosome Xq21.3/Yp11.2 homology block. It is located close to translocation breakpoints associated with premature ovarian failure, and is therefore a potential candidate gene for this disorder. [provided by RefSeq, May 2010]

PABPC5 Gene-Disease associations (from GenCC):

Tourette syndrome
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

PABPC5 links:

Genome browser will be placed here

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=0.07300866).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PABPC5	NM_080832.3 link	c.13G>A	p.Glu5Lys	missense_variant	Exon 2 of 2	ENST00000312600.4	NP_543022.1	Q96DU9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PABPC5	ENST00000312600.4 link	c.13G>A	p.Glu5Lys	missense_variant	Exon 2 of 2	1	NM_080832.3	ENSP00000308012.3		Q96DU9-1
PABPC5	ENST00000373105.1 link	c.-31-449G>A		intron_variant	Intron 1 of 1	2		ENSP00000362197.1		Q5JQF3

Frequencies

GnomAD3 genomes

AF:

0.00000899

AC:

AN:

111173

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000284

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:

0.0000401

AC:

AN:

174722

AF XY:

0.0000333

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000512

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000642

AC:

AN:

1091164

Hom.:

Cov.:

AF XY:

0.00000280

AC XY:

AN XY:

357734

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26257

American (AMR)

AF:

0.00

AC:

AN:

34653

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18960

East Asian (EAS)

AF:

0.000200

AC:

AN:

30068

South Asian (SAS)

AF:

0.00

AC:

AN:

53070

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4089

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

837916

Other (OTH)

AF:

0.00

AC:

AN:

45757

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.00000899

AC:

AN:

111173

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33399

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30520

American (AMR)

AF:

0.00

AC:

AN:

10477

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2647

East Asian (EAS)

AF:

0.000284

AC:

AN:

3519

South Asian (SAS)

AF:

0.00

AC:

AN:

2600

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6001

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53017

Other (OTH)

AF:

0.00

AC:

AN:

1470

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.775

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 03, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.13G>A (p.E5K) alteration is located in exon 2 (coding exon 1) of the PABPC5 gene. This alteration results from a G to A substitution at nucleotide position 13, causing the glutamic acid (E) at amino acid position 5 to be replaced by a lysine (K). 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

0.091

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.044

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.85

M_CAP

Benign

0.054

MetaRNN

Benign

0.073

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

5.0

PrimateAI

Uncertain

0.73

PROVEAN

Benign

0.12

REVEL

Benign

0.091

Sift

Benign

0.50

Sift4G

Benign

0.73

Polyphen

0.24

Vest4

0.29

MutPred

0.31

Gain of MoRF binding (P = 0.0019);

MVP

0.60

MPC

1.0

ClinPred

0.10

GERP RS

4.7

Varity_R

0.31

gMVP

0.68

Mutation Taster

=95/5

polymorphism

(source)

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

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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