Genetic Variant ZNF84:p.Ala607Gly (chr12-133058535-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001289971.2(ZNF84):c.1820C>G(p.Ala607Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000522 in 1,613,982 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00052 ( 3 hom. )

Consequence

ZNF84
NM_001289971.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.326

Variant links:

Genes affected

ZNF84 (HGNC:13159): (zinc finger protein 84) 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 by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF84 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0516015).

BS2

High Homozygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF84	NM_001289971.2 link	c.1820C>G	p.Ala607Gly	missense_variant	Exon 5 of 5	ENST00000539354.6	NP_001276900.1	P51523

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF84	ENST00000539354.6 link	c.1820C>G	p.Ala607Gly	missense_variant	Exon 5 of 5	1	NM_001289971.2	ENSP00000445549.1		P51523

Frequencies

GnomAD3 genomes

AF:

0.000546

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.000959

GnomAD4 exome

AF:

0.000520

AC:

760

AN:

1461726

Hom.:

Cov.:

AF XY:

0.000535

AC XY:

389

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.000515

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000800

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000526

Gnomad4 OTH exome

AF:

0.000662

GnomAD4 genome

AF:

0.000545

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000735

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.000641

Hom.:

Bravo

AF:

0.000578

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 18, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1820C>G (p.A607G) alteration is located in exon 5 (coding exon 4) of the ZNF84 gene. This alteration results from a C to G substitution at nucleotide position 1820, causing the alanine (A) at amino acid position 607 to be replaced by a glycine (G). 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

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.056

T;.;T;T

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.62

T;T;.;.

M_CAP

Benign

0.0093

MetaRNN

Benign

0.052

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.80

N;.;N;N

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-2.3

N;N;N;N

REVEL

Benign

0.051

Sift

Benign

0.052

T;D;T;T

Sift4G

Benign

0.11

T;T;T;T

Polyphen

0.0010

B;.;B;B

Vest4

0.16

MutPred

0.46

Gain of catalytic residue at C604 (P = 0.0523);.;Gain of catalytic residue at C604 (P = 0.0523);Gain of catalytic residue at C604 (P = 0.0523);

MVP

0.12

ClinPred

0.25

GERP RS

2.8

Varity_R

0.17

gMVP

0.19

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