chr15-68146593-G-T

Variant names:

• chr15-68146593-G-T
• rs763915443
• NM_016166.3:c.721G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016166.3(PIAS1):​c.721G>T​(p.Val241Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,364 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PIAS1 NM_016166.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIAS1	NM_016166.3	c.721G>T	p.Val241Leu	missense_variant	Exon 6 of 14	ENST00000249636.11	NP_057250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIAS1	ENST00000249636.11	c.721G>T	p.Val241Leu	missense_variant	Exon 6 of 14	1	NM_016166.3	ENSP00000249636.6
PIAS1	ENST00000545237.1	c.727G>T	p.Val243Leu	missense_variant	Exon 7 of 15	2		ENSP00000438574.1
PIAS1	ENST00000564009.1	n.-69G>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 249036 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135090

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460364 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 726530

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.28
Sift	Benign	0.069	T;T
Sift4G	Uncertain	0.020	D;D
Polyphen		0.89	P;.
Vest4		0.69
MutPred		0.22		Loss of ubiquitination at K238 (P = 0.1179);.;
MVP		0.64
MPC		1.6
ClinPred		0.81	D
GERP RS		5.5
Varity_R		0.38
gMVP		0.62

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

Other links and lift over

dbSNP: rs763915443; hg19: chr15-68438931; COSMIC: COSV51030394; COSMIC: COSV51030394;