15-68141938-T-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_016166.3(PIAS1):c.470-8T>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,583,410 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0023 (7 hom.)
• Consequence: PIAS1 NM_016166.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001053
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.187

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 15-68141938-T-G is Benign according to our data. Variant chr15-68141938-T-G is described in ClinVar as [Benign]. Clinvar id is 1657370.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 198 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIAS1	NM_016166.3	c.470-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000249636.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIAS1	ENST00000249636.11	c.470-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_016166.3	P1
PIAS1	ENST00000545237.1	c.476-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2
PIAS1	ENST00000562190.1	c.*560-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		3
PIAS1	ENST00000564915.5	c.*36-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 198 AN: 152132 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00231

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00124 AC: 270 AN: 217472 Hom.: 0 AF XY: 0.00136 AC XY: 159 AN XY: 117202

Gnomad AFR exome AF: 0.000520

Gnomad AMR exome AF: 0.000642

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000149

Gnomad FIN exome AF: 0.000703

Gnomad NFE exome AF: 0.00229

Gnomad OTH exome AF: 0.00128

GnomAD4 exome AF: 0.00228 AC: 3268 AN: 1431160 Hom.: 7 Cov.: 29 AF XY: 0.00210 AC XY: 1495 AN XY: 710550

Gnomad4 AFR exome AF: 0.000424

Gnomad4 AMR exome AF: 0.000862

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000109

Gnomad4 FIN exome AF: 0.000768

Gnomad4 NFE exome AF: 0.00282

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.00130 AC: 198 AN: 152250 Hom.: 2 Cov.: 31 AF XY: 0.00120 AC XY: 89 AN XY: 74450

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00231

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00188 Hom.: 1

Bravo AF: 0.00135

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	19
Dann	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0011
dbscSNV1_RF	Benign	0.050
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.43		Position offset: -24
DS_AL_spliceai		0.20		Position offset: 8

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200194874; hg19: chr15-68434276;