Genetic Variant PIAS1:p.Ser106Ser (chr15-68086599-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_016166.3(PIAS1):c.318G>A(p.Ser106Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000511 in 1,613,770 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00087 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 6 hom. )

Consequence

PIAS1
NM_016166.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.214

Publications

5 publications found

Variant links:

Genes affected

PIAS1 (HGNC:2752): (protein inhibitor of activated STAT 1) This gene encodes a member of the protein inhibitor of activated STAT (PIAS) family. PIAS proteins function as SUMO E3 ligases and play important roles in many cellular processes by mediating the sumoylation of target proteins. This protein plays a central role as a transcriptional coregulator of numerous cellular pathways includign the STAT1 and nuclear factor kappaB pathways. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

PIAS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 15-68086599-G-A is Benign according to our data. Variant chr15-68086599-G-A is described in ClinVar as Benign. ClinVar VariationId is 1563059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.214 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000874 (133/152130) while in subpopulation EAS AF = 0.0218 (113/5178). AF 95% confidence interval is 0.0186. There are 3 homozygotes in GnomAd4. There are 60 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 133 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016166.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIAS1	NM_016166.3	MANE Select	c.318G>A	p.Ser106Ser	synonymous	Exon 2 of 14	NP_057250.1	O75925-1
	PIAS1	NM_001320687.1		c.324G>A	p.Ser108Ser	synonymous	Exon 3 of 15	NP_001307616.1	O75925-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIAS1	ENST00000249636.11	TSL:1 MANE Select	c.318G>A	p.Ser106Ser	synonymous	Exon 2 of 14	ENSP00000249636.6	O75925-1
PIAS1	ENST00000899735.1		c.318G>A	p.Ser106Ser	synonymous	Exon 2 of 15	ENSP00000569794.1
PIAS1	ENST00000899737.1		c.420G>A	p.Ser140Ser	synonymous	Exon 3 of 15	ENSP00000569796.1

Frequencies

GnomAD3 genomes

AF:

0.000875

AC:

133

AN:

152012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0218

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.00155

AC:

386

AN:

249144

AF XY:

0.00138

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0210

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000661

GnomAD4 exome

AF:

0.000473

AC:

692

AN:

1461640

Hom.:

Cov.:

AF XY:

0.000448

AC XY:

326

AN XY:

727110

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0139

AC:

550

AN:

39700

South Asian (SAS)

AF:

0.000128

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111808

Other (OTH)

AF:

0.00195

AC:

118

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

145

193

241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000874

AC:

133

AN:

152130

Hom.:

Cov.:

AF XY:

0.000807

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41512

American (AMR)

AF:

0.000131

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.0218

AC:

113

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68012

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.000459

Hom.:

Bravo

AF:

0.00103

Asia WGS

AF:

0.00549

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

9.5

(source)

DANN

Benign

0.67

PhyloP100

0.21

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over