Genetic Variant ZNF479:p.Arg280Cys (chr7-57120577-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001370129.2(ZNF479):c.838C>T(p.Arg280Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000391 in 1,610,176 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 (★).

Frequency

Genomes: 𝑓 0.000081 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

ZNF479
NM_001370129.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.25

Variant links:

Genes affected

ZNF479 (HGNC:23258): (zinc finger protein 479) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription, DNA-templated. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF479 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.054138243).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF479	NM_001370129.2 link	c.838C>T	p.Arg280Cys	missense_variant	Exon 4 of 4	ENST00000319636.10	NP_001357058.1
ZNF479	NM_033273.3 link	c.838C>T	p.Arg280Cys	missense_variant	Exon 5 of 5		NP_150376.1	Q96JC4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF479	ENST00000319636.10 link	c.838C>T	p.Arg280Cys	missense_variant	Exon 4 of 4	1	NM_001370129.2	ENSP00000324518.6		Q96JC4
ZNF479	ENST00000331162.8 link	c.838C>T	p.Arg280Cys	missense_variant	Exon 5 of 5	1		ENSP00000333776.4		Q96JC4

Frequencies

GnomAD3 genomes

AF:

0.0000808

AC:

AN:

148600

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000202

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000397

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000297

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000604

AC:

AN:

248504

Hom.:

AF XY:

0.0000667

AC XY:

AN XY:

134976

show subpopulations

Gnomad AFR exome

AF:

0.000196

Gnomad AMR exome

AF:

0.0000581

Gnomad ASJ exome

AF:

0.0000997

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1461454

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727022

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000807

AC:

AN:

148722

Hom.:

Cov.:

AF XY:

0.0000827

AC XY:

AN XY:

72560

show subpopulations

Gnomad4 AFR

AF:

0.000124

Gnomad4 AMR

AF:

0.000201

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000398

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000297

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000387

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000237

AC:

ExAC

AF:

0.0000496

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.838C>T (p.R280C) alteration is located in exon 5 (coding exon 4) of the ZNF479 gene. This alteration results from a C to T substitution at nucleotide position 838, causing the arginine (R) at amino acid position 280 to be replaced by a cysteine (C). 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

0.24

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.68

CADD

Benign

7.5

DANN

Benign

0.56

DEOGEN2

Benign

0.033

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.10

.;T

M_CAP

Benign

0.00094

MetaRNN

Benign

0.054

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

M;M

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.4

D;.

REVEL

Benign

0.029

Sift

Benign

0.14

T;.

Sift4G

Benign

0.16

T;T

Polyphen

0.0040

B;B

Vest4

0.079

MVP

0.24

MPC

1.2

ClinPred

0.022

GERP RS

-0.69

Varity_R

0.083

gMVP

0.011

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