22-31344924-G-A

Position:

• chr22-31344924-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_014323.3(PATZ1):​c.679C>T​(p.Pro227Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PATZ1 NM_014323.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.49

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09804198).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PATZ1	NM_014323.3	c.679C>T	p.Pro227Ser	missense_variant	1/5	ENST00000266269.10
PATZ1	NM_032050.2	c.679C>T	p.Pro227Ser	missense_variant	1/4
PATZ1	NM_032051.2	c.679C>T	p.Pro227Ser	missense_variant	1/3
PATZ1	NM_032052.2	c.679C>T	p.Pro227Ser	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PATZ1	ENST00000266269.10	c.679C>T	p.Pro227Ser	missense_variant	1/5	1	NM_014323.3	P1
PATZ1	ENST00000351933.8	c.679C>T	p.Pro227Ser	missense_variant	1/4	1
PATZ1	ENST00000215919.3	c.679C>T	p.Pro227Ser	missense_variant	1/3	1
PATZ1	ENST00000405309.7	c.679C>T	p.Pro227Ser	missense_variant	1/5	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249820 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135418

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461234 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726922

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

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

Jul 11, 2023

The c.679C>T (p.P227S) alteration is located in exon 1 (coding exon 1) of the PATZ1 gene. This alteration results from a C to T substitution at nucleotide position 679, causing the proline (P) at amino acid position 227 to be replaced by a serine (S). 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	0.16
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.058	T;.;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.013
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.098	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Benign	0.098
Sift	Benign	0.030	D;T;T;T
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.98	D;P;B;B
Vest4		0.047
MutPred		0.49		Loss of catalytic residue at P227 (P = 0.032);Loss of catalytic residue at P227 (P = 0.032);Loss of catalytic residue at P227 (P = 0.032);Loss of catalytic residue at P227 (P = 0.032);
MVP		0.30
MPC		0.93
ClinPred		0.25	T
GERP RS		4.4
Varity_R		0.11
gMVP		0.71

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: rs779345295; hg19: chr22-31740910;