rs150829393

chr15-84799209-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014630.3(ZNF592):c.3136G>A(p.Gly1046Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: ZNF592 NM_014630.3 missense, splice_region
• Scores: Splicing: ADA: 0.7041
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.65

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2516362).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF592	NM_014630.3	c.3136G>A	p.Gly1046Arg	missense_variant, splice_region_variant	9/11	ENST00000560079.7
ZNF592	XM_005254996.4	c.3136G>A	p.Gly1046Arg	missense_variant, splice_region_variant	8/10
ZNF592	XM_011522246.3	c.3136G>A	p.Gly1046Arg	missense_variant, splice_region_variant	9/11
ZNF592	XM_011522247.3	c.3136G>A	p.Gly1046Arg	missense_variant, splice_region_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF592	ENST00000560079.7	c.3136G>A	p.Gly1046Arg	missense_variant, splice_region_variant	9/11	1	NM_014630.3	P1
ZNF592	ENST00000559607.1	c.*548G>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	7/9	1
ZNF592	ENST00000299927.4	c.3136G>A	p.Gly1046Arg	missense_variant, splice_region_variant	6/8	2		P1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000127 AC: 32 AN: 251438 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135890

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000103 AC: 150 AN: 1461830 Hom.: 0 Cov.: 32 AF XY: 0.000106 AC XY: 77 AN XY: 727216

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000108

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74330

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000140 AC: 17

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Galloway-Mowat syndrome 1 Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Jun 29, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.024	T;T
Eigen	Benign	-0.073
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.46	N;N
MutationTaster	Benign	0.82	A;A
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.74	N;N
Sift	Benign	0.16	T;T
Sift4G	Benign	0.42	T;T
Polyphen		0.36	B;B
Vest4		0.60
MutPred		0.24		Gain of disorder (P = 0.0398);Gain of disorder (P = 0.0398);
MVP		0.65
MPC		0.39
ClinPred		0.027	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.055
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.70
dbscSNV1_RF	Benign	0.42
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: rs150829393; hg19: chr15-85342440; COSMIC: COSV55435825; COSMIC: COSV55435825;