dbSNP rs777936918: ZNF462:p.Ser138Arg (chr9-106924326-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021224.6(ZNF462):c.414T>A(p.Ser138Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ZNF462
NM_021224.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.74

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08145061).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF462	NM_021224.6 link	c.414T>A	p.Ser138Arg	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.414T>A	p.Ser138Arg	missense_variant	Exon 3 of 13	1	NM_021224.6	ENSP00000277225.5		Q96JM2-1
ZNF462	ENST00000472574.1 link	c.280+134T>A		intron_variant	Intron 3 of 3	4		ENSP00000476222.1		U3KQU3

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151492

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251344

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112002

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

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:

0.00000660

AC:

AN:

151492

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73952

show subpopulations

African (AFR)

AF:

0.0000243

AC:

AN:

41214

American (AMR)

AF:

0.00

AC:

AN:

15198

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4774

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10524

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67846

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Nov 05, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.414T>A (p.S138R) alteration is located in exon 3 (coding exon 2) of the ZNF462 gene. This alteration results from a T to A substitution at nucleotide position 414, causing the serine (S) at amino acid position 138 to be replaced by an arginine (R). 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

0.30

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.016

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.79

M_CAP

Benign

0.021

MetaRNN

Benign

0.081

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.90

PhyloP100

2.7

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.91

REVEL

Benign

0.096

Sift

Benign

0.20

Sift4G

Benign

0.28

Polyphen

0.089

Vest4

0.36

MutPred

0.21

Loss of sheet (P = 0.0104);

MVP

0.043

MPC

0.41

ClinPred

0.044

GERP RS

4.7

Varity_R

0.035

gMVP

0.31

Mutation Taster

=85/15

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over