9-106924489-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021224.6(ZNF462):c.577A>G(p.Thr193Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000372 in 1,614,162 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0022 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

ZNF462
NM_021224.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0260

Publications

2 publications found

Variant links:

Genes affected

ZNF462 (HGNC:21684): (zinc finger protein 462) The protein encoded by this gene belongs to C2H2-type zinc finger family of proteins. It contains multiple C2H2-type zinc fingers and may be involved in transcriptional regulation. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2016]

ZNF462 Gene-Disease associations (from GenCC):

Weiss-Kruszka syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Illumina, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia

ZNF462 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003620118).

BP6

Variant 9-106924489-A-G is Benign according to our data. Variant chr9-106924489-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 712033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-106924489-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 712033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-106924489-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 712033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-106924489-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 712033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-106924489-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 712033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00217 (331/152296) while in subpopulation AFR AF = 0.00765 (318/41580). AF 95% confidence interval is 0.00696. There are 4 homozygotes in GnomAd4. There are 161 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 331 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF462	NM_021224.6 link	c.577A>G	p.Thr193Ala	missense_variant	Exon 3 of 13	ENST00000277225.10	NP_067047.4	Q96JM2-1Q63HJ5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF462	ENST00000277225.10 link	c.577A>G	p.Thr193Ala	missense_variant	Exon 3 of 13	1	NM_021224.6	ENSP00000277225.5		Q96JM2-1
ZNF462	ENST00000472574.1 link	c.280+297A>G		intron_variant	Intron 3 of 3	4		ENSP00000476222.1		U3KQU3

Frequencies

GnomAD3 genomes

AF:

0.00219

AC:

333

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.00287

GnomAD2 exomes

AF:

0.000558

AC:

140

AN:

250904

AF XY:

0.000449

show subpopulations

Gnomad AFR exome

AF:

0.00782

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000185

AC:

270

AN:

1461866

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

117

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.00678

AC:

227

AN:

33480

American (AMR)

AF:

0.000313

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1112010

Other (OTH)

AF:

0.000364

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00217

AC:

331

AN:

152296

Hom.:

Cov.:

AF XY:

0.00216

AC XY:

161

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00765

AC:

318

AN:

41580

American (AMR)

AF:

0.000327

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68018

Other (OTH)

AF:

0.00284

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000817

Hom.:

Bravo

AF:

0.00230

ESP6500AA

AF:

0.00658

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000708

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Feb 10, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.029

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.010

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.49

M_CAP

Benign

0.0065

MetaRNN

Benign

0.0036

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.55

PhyloP100

-0.026

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.36

REVEL

Benign

0.073

Sift

Benign

0.38

Sift4G

Benign

0.36

Polyphen

0.0

Vest4

0.061

MVP

0.068

MPC

0.32

ClinPred

1.0

GERP RS

-9.0

Varity_R

0.016

gMVP

0.10

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over