Variant X-69162074-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001032396.4(PJA1):c.1000A>G(p.Ser334Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000629 in 1,208,916 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 26 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., 6 hem., cov: 22)

Exomes 𝑓: 0.000039 ( 0 hom. 20 hem. )

Consequence

PJA1
NM_001032396.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.16

Variant links:

Genes affected

PJA1 (HGNC:16648): (praja ring finger ubiquitin ligase 1) This gene encodes an enzyme that has E2-dependent E3 ubiquitin-protein ligase activity. This enzyme belongs to a class of ubiquitin ligases that include a RING finger motif, and it can interact with the E2 ubiquitin-conjugating enzyme UbcH5B. This gene is located in an area of chromosome X where several X-linked cognitive disability disorders have been associated, and it has also been found as part of a contiguous gene deletion associated with craniofrontonasal syndrome, though a direct link to any disorder has yet to be demonstrated. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

PJA1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.040031224).

BS2

High Hemizygotes in GnomAd4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PJA1	NM_001032396.4 linkuse as main transcript	c.1000A>G	p.Ser334Gly	missense_variant	2/2	ENST00000374571.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PJA1	ENST00000374571.5 linkuse as main transcript	c.1000A>G	p.Ser334Gly	missense_variant	2/2	1	NM_001032396.4	P2	Q8NG27-3

Frequencies

GnomAD3 genomes

AF:

0.000298

AC:

AN:

110654

Hom.:

Cov.:

AF XY:

0.000183

AC XY:

AN XY:

32868

show subpopulations

Gnomad AFR

AF:

0.000921

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000379

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:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000765

AC:

AN:

183022

Hom.:

AF XY:

0.0000886

AC XY:

AN XY:

67692

show subpopulations

Gnomad AFR exome

AF:

0.000768

Gnomad AMR exome

AF:

0.0000730

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:

0.0000245

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000392

AC:

AN:

1098206

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

363566

show subpopulations

Gnomad4 AFR exome

AF:

0.000909

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000107

Gnomad4 OTH exome

AF:

0.000130

GnomAD4 genome

AF:

0.000298

AC:

AN:

110710

Hom.:

Cov.:

AF XY:

0.000182

AC XY:

AN XY:

32934

show subpopulations

Gnomad4 AFR

AF:

0.000919

Gnomad4 AMR

AF:

0.000379

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000189

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000593

Hom.:

Bravo

AF:

0.000317

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2021

The c.1165A>G (p.S389G) alteration is located in exon 2 (coding exon 1) of the PJA1 gene. This alteration results from a A to G substitution at nucleotide position 1165, causing the serine (S) at amino acid position 389 to be replaced by a glycine (G). 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

0.11

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.76

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.31

T;.;T;.

FATHMM_MKL

Uncertain

0.94

M_CAP

Benign

0.016

MetaRNN

Benign

0.040

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.7

M;.;M;.

MutationTaster

Benign

0.68

D;D;D;D

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-1.8

N;N;N;N

REVEL

Benign

0.090

Sift

Benign

0.083

T;T;T;T

Sift4G

Benign

0.24

T;T;T;T

Polyphen

0.13

B;P;B;.

Vest4

0.16

MVP

0.46

MPC

0.60

ClinPred

0.058

GERP RS

2.3

Varity_R

0.12

gMVP

0.13

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.

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