NM_144631.6:c.781G>A

Variant names:

• chr2-27378485-C-T
• rs61742428
• NM_144631.6:c.781G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_144631.6(ZNF513):​c.781G>A​(p.Val261Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000379 in 1,614,148 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V261L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: ZNF513 NM_144631.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.136
• Publications: 4 publications found

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]

ZNF513 Gene-Disease associations (from GenCC):

• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa 58

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005774379).
• BP6: Variant 2-27378485-C-T is Benign according to our data. Variant chr2-27378485-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167864.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=1}.
• BS2: High AC in GnomAd4 at 297 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF513	NM_144631.6	c.781G>A	p.Val261Met	missense_variant	Exon 3 of 4	ENST00000323703.11	NP_653232.3
ZNF513	NM_001201459.2	c.595G>A	p.Val199Met	missense_variant	Exon 2 of 3		NP_001188388.1
ZNF513	XM_005264143.4	c.277G>A	p.Val93Met	missense_variant	Exon 2 of 3		XP_005264200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF513	ENST00000323703.11	c.781G>A	p.Val261Met	missense_variant	Exon 3 of 4	1	NM_144631.6	ENSP00000318373.6
ZNF513	ENST00000407879.1	c.595G>A	p.Val199Met	missense_variant	Exon 2 of 3	1		ENSP00000384874.1
ZNF513	ENST00000491924.1	n.241G>A		non_coding_transcript_exon_variant	Exon 2 of 3	5
ZNF513	ENST00000436006.1	c.*246G>A		downstream_gene_variant		2		ENSP00000394226.1

Frequencies

GnomAD3 genomes AF: 0.00195 AC: 297 AN: 152268 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00668

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000524 AC: 130 AN: 248322 AF XY: 0.000408

Gnomad AFR exome AF: 0.00695

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000215 AC: 315 AN: 1461762 Hom.: 0 Cov.: 33 AF XY: 0.000193 AC XY: 140 AN XY: 727186

African (AFR) AF: 0.00684 AC: 229 AN: 33480

American (AMR) AF: 0.000470 AC: 21 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53296

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1112006

Other (OTH) AF: 0.000513 AC: 31 AN: 60396

GnomAD4 genome AF: 0.00195 AC: 297 AN: 152386 Hom.: 2 Cov.: 33 AF XY: 0.00189 AC XY: 141 AN XY: 74522

African (AFR) AF: 0.00666 AC: 277 AN: 41596

American (AMR) AF: 0.000980 AC: 15 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68036

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000469 Hom.: 0

Bravo AF: 0.00238

ESP6500AA AF: 0.00659 AC: 29

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000560 AC: 68

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 14, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa 58 Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.0058	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.
PhyloP100		0.14
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.090	N;N
REVEL	Benign	0.070
Sift	Benign	0.25	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.0020	B;.
Vest4		0.27
MVP		0.19
MPC		0.64
ClinPred		0.020	T
GERP RS		3.8
Varity_R		0.049
gMVP		0.20
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs61742428; hg19: chr2-27601352;