Variant 19-4028823-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_015897.4(PIAS4):c.776C>T(p.Thr259Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PIAS4
NM_015897.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.98

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.794

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PIAS4	NM_015897.4 linkuse as main transcript	c.776C>T	p.Thr259Ile	missense_variant	6/11	ENST00000262971.3	NP_056981.2
PIAS4	XM_011528060.3 linkuse as main transcript	c.833C>T	p.Thr278Ile	missense_variant	6/11		XP_011526362.1
PIAS4	XM_017026868.2 linkuse as main transcript	c.203C>T	p.Thr68Ile	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.776C>T	p.Thr259Ile	missense_variant	6/11	1	NM_015897.4	ENSP00000262971.1	Q8N2W9
PIAS4	ENST00000596144.1 linkuse as main transcript	n.*37C>T		downstream_gene_variant		3
PIAS4	ENST00000601439.1 linkuse as main transcript	n.*9C>T		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461376

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727004

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000371

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

PIAS4-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2023

The PIAS4 c.776C>T variant is predicted to result in the amino acid substitution p.Thr259Ile. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.19

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.047

MetaRNN

Pathogenic

0.79

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.8

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.32

Sift

Benign

0.041

Sift4G

Benign

0.093

Polyphen

0.89

Vest4

0.84

MVP

0.82

MPC

1.8

ClinPred

0.89

GERP RS

4.8

Varity_R

0.25

gMVP

0.69

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