Variant chr18-25225265-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The NM_015461.3(ZNF521):c.2653A>G(p.Met885Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000248 in 1,614,140 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 1 hom. )

Consequence

ZNF521
NM_015461.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.67

Variant links:

Genes affected

ZNF521 (HGNC:24605): (zinc finger protein 521) Enables protein domain specific binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within neuron fate commitment. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF521 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP2

Missense variant where missense usually causes diseases, ZNF521

BS2

High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF521	NM_015461.3 linkuse as main transcript	c.2653A>G	p.Met885Val	missense_variant	4/8	ENST00000361524.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ZNF521	ENST00000361524.8 linkuse as main transcript	c.2653A>G	p.Met885Val	missense_variant	4/8	1	NM_015461.3	P1
ZNF521	ENST00000584787.5 linkuse as main transcript	c.1993A>G	p.Met665Val	missense_variant	3/7	1
ZNF521	ENST00000399425.6 linkuse as main transcript	c.2653A>G	p.Met885Val	missense_variant, NMD_transcript_variant	4/9	1
ZNF521	ENST00000538137.6 linkuse as main transcript	c.2653A>G	p.Met885Val	missense_variant	4/8	2		P1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000171

AC:

AN:

251278

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000256

AC:

374

AN:

1461874

Hom.:

Cov.:

AF XY:

0.000263

AC XY:

191

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.000281

Gnomad4 NFE exome

AF:

0.000288

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000171

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000248

Hom.:

Bravo

AF:

0.000144

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2023

The c.2653A>G (p.M885V) alteration is located in exon 4 (coding exon 3) of the ZNF521 gene. This alteration results from a A to G substitution at nucleotide position 2653, causing the methionine (M) at amino acid position 885 to be replaced by a valine (V). 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

0.17

BayesDel_addAF

Benign

-0.054

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.13

T;T;T

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.56

D;D;D

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.4

M;.;M

MutationTaster

Benign

0.99

D;D;D

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.1

N;.;.

REVEL

Uncertain

0.36

Sift

Benign

0.49

T;.;.

Sift4G

Benign

0.69

T;T;T

Polyphen

0.98

D;.;D

Vest4

0.76

MVP

0.32

MPC

1.1

ClinPred

0.15

GERP RS

5.8

Varity_R

0.34

gMVP

0.42

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over