22-31344986-A-G

Position:

• chr22-31344986-A-G

Variant summary

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

The NM_014323.3(PATZ1):​c.617T>C​(p.Met206Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PATZ1 NM_014323.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.97

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=0.07242522).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PATZ1	NM_014323.3	c.617T>C	p.Met206Thr	missense_variant	1/5	ENST00000266269.10
PATZ1	NM_032050.2	c.617T>C	p.Met206Thr	missense_variant	1/4
PATZ1	NM_032051.2	c.617T>C	p.Met206Thr	missense_variant	1/3
PATZ1	NM_032052.2	c.617T>C	p.Met206Thr	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PATZ1	ENST00000266269.10	c.617T>C	p.Met206Thr	missense_variant	1/5	1	NM_014323.3	P1
PATZ1	ENST00000351933.8	c.617T>C	p.Met206Thr	missense_variant	1/4	1
PATZ1	ENST00000215919.3	c.617T>C	p.Met206Thr	missense_variant	1/3	1
PATZ1	ENST00000405309.7	c.617T>C	p.Met206Thr	missense_variant	1/5	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461652 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727132

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Mar 21, 2022

The c.617T>C (p.M206T) alteration is located in exon 1 (coding exon 1) of the PATZ1 gene. This alteration results from a T to C substitution at nucleotide position 617, causing the methionine (M) at amino acid position 206 to be replaced by a threonine (T). 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	0.23
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Benign	0.88
DEOGEN2	Benign	0.032	T;.;.;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.86	D;D;D;D
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.072	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;N;N
MutationTaster	Benign	0.93	N;N;N;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.74	N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.089	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.24
MutPred		0.18		Gain of glycosylation at M206 (P = 0.0189);Gain of glycosylation at M206 (P = 0.0189);Gain of glycosylation at M206 (P = 0.0189);Gain of glycosylation at M206 (P = 0.0189);
MVP		0.21
MPC		1.1
ClinPred		0.12	T
GERP RS		4.1
Varity_R		0.17
gMVP		0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-31740972;