2-27377554-G-C

Variant summary

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

The NM_144631.6(ZNF513):c.1617C>G(p.Asp539Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D539G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF513 NM_144631.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.73

Genes affected

ZNF513 (HGNC:26498): (zinc finger protein 513) The protein encoded by this gene is a possible transcriptional regulator involved in retinal development. Defects in this gene can be a cause of autosomal-recessive retinitis pigmentosa. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2011]

SNX17 (HGNC:14979): (sorting nexin 17) This gene encodes a member of the sorting nexin family. Members of this family contain a phox (PX) domain, which is a phosphoinositide binding domain, and are involved in intracellular trafficking. This protein does not contain a coiled coil region, like some family members, but contains a B41 domain. This protein interacts with the cytoplasmic domain of P-selectin, and may function in the intracellular trafficking of P-selectin. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2012]

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=0.16422033).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF513	NM_144631.6	c.1617C>G	p.Asp539Glu	missense_variant	4/4	ENST00000323703.11
SNX17	NM_014748.4			downstream_gene_variant		ENST00000233575.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF513	ENST00000323703.11	c.1617C>G	p.Asp539Glu	missense_variant	4/4	1	NM_144631.6	P4
ZNF513	ENST00000407879.1	c.1431C>G	p.Asp477Glu	missense_variant	3/3	1		A1
SNX17	ENST00000233575.7			downstream_gene_variant		1	NM_014748.4	P1
SNX17	ENST00000537606.5			downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461732 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

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 provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 13, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 539 of the ZNF513 protein (p.Asp539Glu). This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 954448). This variant has not been reported in the literature in individuals affected with ZNF513-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.010	T;.
Eigen	Benign	0.093
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.36	T;T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.
MutationTaster	Benign	0.88	N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.32	N;N
REVEL	Benign	0.081
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.72	P;.
Vest4		0.25
MutPred		0.13		Loss of MoRF binding (P = 0.1118);.;
MVP		0.24
MPC		0.48
ClinPred		0.40	T
GERP RS		3.7
Varity_R		0.31
gMVP		0.16

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: rs1683382282; hg19: chr2-27600421;