22-31326900-T-G

Position:

• chr22-31326900-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014323.3(PATZ1):​c.2055A>C​(p.Glu685Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0245 in 1,611,804 control chromosomes in the GnomAD database, including 4,706 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.044 (544 hom., cov: 32)
  • Exomes 𝑓: 0.022 (4162 hom.)
• Consequence: PATZ1 NM_014323.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.74

Genes affected

PATZ1 (HGNC:13071): (POZ/BTB and AT hook containing zinc finger 1) The protein encoded by this gene contains an A-T hook DNA binding motif which usually binds to other DNA binding structures to play an important role in chromatin modeling and transcription regulation. Its Poz domain is thought to function as a site for protein-protein interaction and is required for transcriptional repression, and the zinc-fingers comprise the DNA binding domain. Since the encoded protein has typical features of a transcription factor, it is postulated to be a repressor of gene expression. In small round cell sarcoma, this gene is fused to EWS by a small inversion of 22q, then the hybrid is thought to be translocated (t(1;22)(p36.1;q12). The rearrangement of chromosome 22 involves intron 8 of EWS and exon 1 of this gene creating a chimeric sequence containing the transactivation domain of EWS fused to zinc finger domain of this protein. This is a distinct example of an intra-chromosomal rearrangement of chromosome 22. Four alternatively spliced transcript variants are described for this gene. [provided by RefSeq, Jul 2008]

PIK3IP1-DT (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002393514).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.352 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PATZ1	NM_014323.3	c.2055A>C	p.Glu685Asp	missense_variant	5/5	ENST00000266269.10	NP_055138.2
PATZ1	NM_032050.2	c.1917A>C	p.Glu639Asp	missense_variant	4/4		NP_114439.1
PATZ1	NM_032052.2	c.*376A>C		3_prime_UTR_variant	5/5		NP_114441.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PATZ1	ENST00000266269.10	c.2055A>C	p.Glu685Asp	missense_variant	5/5	1	NM_014323.3	ENSP00000266269.5
PATZ1	ENST00000351933.8	c.1917A>C	p.Glu639Asp	missense_variant	4/4	1		ENSP00000337520.4
PATZ1	ENST00000405309	c.*376A>C		3_prime_UTR_variant	5/5	1		ENSP00000384173.3
PIK3IP1-DT	ENST00000440456.5	n.201-10768T>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0439 AC: 6675 AN: 152114 Hom.: 536 Cov.: 32

Gnomad AFR AF: 0.0665

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0971

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.366

Gnomad SAS AF: 0.0392

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00238

Gnomad OTH AF: 0.0435

GnomAD3 exomes AF: 0.0586 AC: 14645 AN: 250050 Hom.: 1730 AF XY: 0.0508 AC XY: 6873 AN XY: 135216

Gnomad AFR exome AF: 0.0700

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.0169

Gnomad EAS exome AF: 0.363

Gnomad SAS exome AF: 0.0300

Gnomad FIN exome AF: 0.00334

Gnomad NFE exome AF: 0.00255

Gnomad OTH exome AF: 0.0350

GnomAD4 exome AF: 0.0225 AC: 32775 AN: 1459570 Hom.: 4162 Cov.: 32 AF XY: 0.0218 AC XY: 15815 AN XY: 725902

Gnomad4 AFR exome AF: 0.0700

Gnomad4 AMR exome AF: 0.143

Gnomad4 ASJ exome AF: 0.0197

Gnomad4 EAS exome AF: 0.403

Gnomad4 SAS exome AF: 0.0305

Gnomad4 FIN exome AF: 0.00352

Gnomad4 NFE exome AF: 0.00224

Gnomad4 OTH exome AF: 0.0351

GnomAD4 genome AF: 0.0440 AC: 6699 AN: 152234 Hom.: 544 Cov.: 32 AF XY: 0.0476 AC XY: 3547 AN XY: 74440

Gnomad4 AFR AF: 0.0670

Gnomad4 AMR AF: 0.0970

Gnomad4 ASJ AF: 0.0182

Gnomad4 EAS AF: 0.366

Gnomad4 SAS AF: 0.0384

Gnomad4 FIN AF: 0.00311

Gnomad4 NFE AF: 0.00238

Gnomad4 OTH AF: 0.0431

Alfa AF: 0.0211 Hom.: 622

Bravo AF: 0.0544

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.0631 AC: 278

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.0542 AC: 6579

Asia WGS AF: 0.175 AC: 609 AN: 3478

EpiCase AF: 0.00387

EpiControl AF: 0.00385

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.044	T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T;T
MetaRNN	Benign	0.0024	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.55	N;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.71	N;N
REVEL	Benign	0.11
Sift	Uncertain	0.019	D;D
Sift4G	Benign	0.12	T;T
Polyphen		0.82	P;P
Vest4		0.077
MutPred		0.11		Loss of methylation at K687 (P = 0.06);.;
MPC		2.0
ClinPred		0.019	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.094
gMVP		0.089

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: rs2240424; hg19: chr22-31722886; COSMIC: COSV56743944;