Genetic Variant PIAS4:p.Pro123Pro (chr19-4013264-C-T) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_015897.4(PIAS4):c.369C>T(p.Pro123Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00825 in 1,613,310 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0063 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0085 ( 69 hom. )

Consequence

PIAS4
NM_015897.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.180

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 19-4013264-C-T is Benign according to our data. Variant chr19-4013264-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 771210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.18 with no splicing effect.

BS2

High AC in GnomAd4 at 959 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIAS4	NM_015897.4 link	c.369C>T	p.Pro123Pro	synonymous_variant	Exon 2 of 11	ENST00000262971.3	NP_056981.2
PIAS4	XM_011528060.3 link	c.426C>T	p.Pro142Pro	synonymous_variant	Exon 2 of 11		XP_011526362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PIAS4	ENST00000262971.3 link	c.369C>T	p.Pro123Pro	synonymous_variant	Exon 2 of 11	1	NM_015897.4	ENSP00000262971.1	Q8N2W9
PIAS4	ENST00000593518.1 link	n.372C>T		non_coding_transcript_exon_variant	Exon 2 of 3	4
PIAS4	ENST00000599999.5 link	n.376C>T		non_coding_transcript_exon_variant	Exon 2 of 4	3
PIAS4	ENST00000600566.5 link	n.374C>T		non_coding_transcript_exon_variant	Exon 2 of 4	2

Frequencies

GnomAD3 genomes

AF:

0.00630

AC:

959

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.0138

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0202

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00869

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00604

AC:

1516

AN:

250958

Hom.:

AF XY:

0.00607

AC XY:

825

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00286

Gnomad ASJ exome

AF:

0.0112

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.0180

Gnomad NFE exome

AF:

0.00751

Gnomad OTH exome

AF:

0.00637

GnomAD4 exome

AF:

0.00845

AC:

12347

AN:

1461026

Hom.:

Cov.:

AF XY:

0.00823

AC XY:

5981

AN XY:

726824

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.00353

Gnomad4 ASJ exome

AF:

0.0118

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.000290

Gnomad4 FIN exome

AF:

0.0167

Gnomad4 NFE exome

AF:

0.00939

Gnomad4 OTH exome

AF:

0.00798

GnomAD4 genome

AF:

0.00630

AC:

959

AN:

152284

Hom.:

Cov.:

AF XY:

0.00686

AC XY:

511

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00140

Gnomad4 AMR

AF:

0.00242

Gnomad4 ASJ

AF:

0.0138

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0202

Gnomad4 NFE

AF:

0.00869

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00825

Hom.:

Bravo

AF:

0.00512

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00774

EpiControl

AF:

0.00688

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jun 27, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PIAS4: BP4, BP7 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

7.4

DANN

Benign

0.73

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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