Genetic Variant ZNF496:p.Arg551Gln (chr1-247300631-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032752.3(ZNF496):c.1652G>A(p.Arg551Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

ZNF496
NM_032752.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.00600

Variant links:

Genes affected

ZNF496 (HGNC:23713): (zinc finger protein 496) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific; RNA polymerase II cis-regulatory region sequence-specific DNA binding activity; and protein self-association. Predicted to be involved in positive regulation of transcription, DNA-templated and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within negative regulation of transcription by RNA polymerase II. Predicted to be located in nuclear body. [provided by Alliance of Genome Resources, Apr 2022]

ZNF496 links:

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ACMG classification

Classification made for transcript

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=0.12446675).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF496	NM_032752.3 link	c.1652G>A	p.Arg551Gln	missense_variant	Exon 10 of 10	ENST00000682384.1	NP_116141.1	Q96IT1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF496	ENST00000682384.1 link	c.1652G>A	p.Arg551Gln	missense_variant	Exon 10 of 10		NM_032752.3	ENSP00000507236.1	Q96IT1-1
ZNF496	ENST00000294753.8 link	c.1652G>A	p.Arg551Gln	missense_variant	Exon 9 of 9	1		ENSP00000294753.4	Q96IT1-1
ZNF496	ENST00000461277.2 link	c.1427G>A	p.Arg476Gln	missense_variant	Exon 8 of 8	1		ENSP00000473324.1	A0A0C4DGR5
ZNF496	ENST00000462139.1 link	n.6024G>A		non_coding_transcript_exon_variant	Exon 2 of 2	1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251364

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1461786

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000288

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000163

Hom.:

Bravo

AF:

0.0000718

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1652G>A (p.R551Q) alteration is located in exon 9 (coding exon 7) of the ZNF496 gene. This alteration results from a G to A substitution at nucleotide position 1652, causing the arginine (R) at amino acid position 551 to be replaced by a glutamine (Q). 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

Uncertain

0.36

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.045

T;.

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.0033

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

M;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.81

N;.

REVEL

Benign

0.089

Sift

Benign

0.067

T;.

Sift4G

Benign

0.11

T;T

Polyphen

0.0070

B;.

Vest4

0.083

MVP

0.51

MPC

0.51

ClinPred

0.027

GERP RS

-2.8

Varity_R

0.032

gMVP

0.13

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