19-4013151-A-G

Position:

• chr19-4013151-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015897.4(PIAS4):​c.256A>G​(p.Met86Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIAS4 NM_015897.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.376

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.026591003).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIAS4	NM_015897.4	c.256A>G	p.Met86Val	missense_variant	2/11	ENST00000262971.3	NP_056981.2
PIAS4	XM_011528060.3	c.313A>G	p.Met105Val	missense_variant	2/11		XP_011526362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIAS4	ENST00000262971.3	c.256A>G	p.Met86Val	missense_variant	2/11	1	NM_015897.4	ENSP00000262971.1
PIAS4	ENST00000593518.1	n.259A>G		non_coding_transcript_exon_variant	2/3	4
PIAS4	ENST00000599999.5	n.263A>G		non_coding_transcript_exon_variant	2/4	3
PIAS4	ENST00000600566.5	n.261A>G		non_coding_transcript_exon_variant	2/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 12, 2021

The c.256A>G (p.M86V) alteration is located in exon 2 (coding exon 2) of the PIAS4 gene. This alteration results from a A to G substitution at nucleotide position 256, causing the methionine (M) at amino acid position 86 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	8.2
DANN	Benign	0.67
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.20	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.061
Sift	Benign	0.81	T
Sift4G	Benign	0.60	T
Polyphen		0.0	B
Vest4		0.044
MutPred		0.24		Gain of sheet (P = 0.0477);
MVP		0.21
MPC		0.73
ClinPred		0.019	T
GERP RS		-0.79
Varity_R		0.027
gMVP		0.33

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: rs1324632961; hg19: chr19-4013149;