Variant 19-4028807-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_015897.4(PIAS4):c.760G>A(p.Ala254Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000283 in 1,613,452 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

PIAS4
NM_015897.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.86

Variant links:

Genes affected

PIAS4 (HGNC:17002): (protein inhibitor of activated STAT 4) Enables SUMO ligase activity and ubiquitin protein ligase binding activity. Involved in negative regulation of transcription, DNA-templated; positive regulation of protein sumoylation; and protein sumoylation. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

PIAS4 links:

PIAS4 (HGNC:):

PIAS4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13210943).

BS2

High AC in GnomAd4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PIAS4	NM_015897.4 linkuse as main transcript	c.760G>A	p.Ala254Thr	missense_variant	6/11	ENST00000262971.3	NP_056981.2
PIAS4	XM_011528060.3 linkuse as main transcript	c.817G>A	p.Ala273Thr	missense_variant	6/11		XP_011526362.1
PIAS4	XM_017026868.2 linkuse as main transcript	c.187G>A	p.Ala63Thr	missense_variant	3/8		XP_016882357.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PIAS4	ENST00000262971.3 linkuse as main transcript	c.760G>A	p.Ala254Thr	missense_variant	6/11	1	NM_015897.4	ENSP00000262971.1	Q8N2W9
PIAS4	ENST00000601439.1 linkuse as main transcript	n.228G>A		non_coding_transcript_exon_variant	2/2	3
PIAS4	ENST00000596144.1 linkuse as main transcript	n.*21G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000140

AC:

AN:

250502

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

135710

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.0000997

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000257

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000291

AC:

425

AN:

1461358

Hom.:

Cov.:

AF XY:

0.000259

AC XY:

188

AN XY:

727004

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.000367

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000210

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000426

Hom.:

Bravo

AF:

0.000196

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000296

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.760G>A (p.A254T) alteration is located in exon 6 (coding exon 6) of the PIAS4 gene. This alteration results from a G to A substitution at nucleotide position 760, causing the alanine (A) at amino acid position 254 to be replaced by a threonine (T). 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

0.15

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.052

Eigen

Benign

-0.16

Eigen_PC

Benign

0.044

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.022

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.83

PrimateAI

Uncertain

0.79

PROVEAN

Benign

1.6

REVEL

Benign

0.15

Sift

Benign

0.66

Sift4G

Benign

1.0

Polyphen

0.27

Vest4

0.21

MVP

0.49

MPC

1.1

ClinPred

0.14

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.064

gMVP

0.43

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