15-84782844-T-G

Variant summary

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

The NM_014630.3(ZNF592):c.169T>G(p.Ser57Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,614,090 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: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: ZNF592 NM_014630.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:2
• Conservation: PhyloP100: 2.30

Genes affected

ZNF592 (HGNC:28986): (zinc finger protein 592) This gene is thought to play a role in a complex developmental pathway and the regulation of genes involved in cerebellar development. Mutations in this gene have been associated with autosomal recessive spinocerebellar ataxia. [provided by RefSeq, Jan 2011]

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=0.015789181).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF592	NM_014630.3	c.169T>G	p.Ser57Ala	missense_variant	4/11	ENST00000560079.7
ZNF592	XM_005254996.4	c.169T>G	p.Ser57Ala	missense_variant	3/10
ZNF592	XM_011522246.3	c.169T>G	p.Ser57Ala	missense_variant	4/11
ZNF592	XM_011522247.3	c.169T>G	p.Ser57Ala	missense_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF592	ENST00000560079.7	c.169T>G	p.Ser57Ala	missense_variant	4/11	1	NM_014630.3	P1
ZNF592	ENST00000559607.1	c.169T>G	p.Ser57Ala	missense_variant, NMD_transcript_variant	2/9	1
ZNF592	ENST00000299927.4	c.169T>G	p.Ser57Ala	missense_variant	1/8	2		P1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000223 AC: 56 AN: 251484 Hom.: 0 AF XY: 0.000228 AC XY: 31 AN XY: 135920

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000142 AC: 208 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.000146 AC XY: 106 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000109

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74436

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000163 Hom.: 0

Bravo AF: 0.000325

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2022

The c.169T>G (p.S57A) alteration is located in exon 4 (coding exon 1) of the ZNF592 gene. This alteration results from a T to G substitution at nucleotide position 169, causing the serine (S) at amino acid position 57 to be replaced by an alanine (A). 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	0.060
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	15
Dann	Uncertain	0.98
DEOGEN2	Benign	0.012	T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.016	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.79	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.080	N;N
Sift	Benign	0.51	T;T
Sift4G	Benign	0.71	T;T
Polyphen		0.0010	B;B
Vest4		0.17
MVP		0.043
MPC		0.22
ClinPred		0.024	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.087
gMVP		0.054

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs145206161; hg19: chr15-85326075;