19-4028595-G-C

Variant names:

• chr19-4028595-G-C
• rs141113403
• NM_015897.4:c.667G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015897.4(PIAS4):​c.667G>C​(p.Val223Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V223I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: PIAS4 NM_015897.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.59
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16632989).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015897.4. 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
	PIAS4	NM_015897.4	MANE Select	c.667G>C	p.Val223Leu	missense	Exon 5 of 11	NP_056981.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIAS4	ENST00000262971.3	TSL:1 MANE Select	c.667G>C	p.Val223Leu	missense	Exon 5 of 11	ENSP00000262971.1	Q8N2W9
	PIAS4	ENST00000932795.1		c.727G>C	p.Val243Leu	missense	Exon 6 of 12	ENSP00000602854.1
	PIAS4	ENST00000963735.1		c.706G>C	p.Val236Leu	missense	Exon 5 of 11	ENSP00000633794.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.36	N
PhyloP100		4.6
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	1.8	N
REVEL	Benign	0.083
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.037	B
Vest4		0.32
MutPred		0.63		Loss of phosphorylation at Y220 (P = 0.1521)
MVP		0.36
MPC		1.1
ClinPred		0.94	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.081
gMVP		0.54
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs141113403; hg19: chr19-4028593;