Genetic Variant ZNF804A:p.Gln261Leu (chr2-184936178-A-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_194250.2(ZNF804A):c.782A>T(p.Gln261Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.629 in 1,613,750 control chromosomes in the GnomAD database, including 322,495 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.60 ( 28002 hom., cov: 32)

Exomes 𝑓: 0.63 ( 294493 hom. )

Consequence

ZNF804A
NM_194250.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.151

Publications

35 publications found

Variant links:

Genes affected

ZNF804A (HGNC:21711): (zinc finger protein 804A) The protein encoded by this gene is a zinc finger binding protein. Polymorphisms in this gene, especially rs1344706, are thought to confer increased susceptibility to schizophrenia, bipolar disorder, and heroin addiciton. [provided by RefSeq, Nov 2015]

ZNF804A Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ZNF804A 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=1.1170101E-6).

BP6

Variant 2-184936178-A-T is Benign according to our data. Variant chr2-184936178-A-T is described in ClinVar as [Benign]. Clinvar id is 1221151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.81 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF804A	NM_194250.2 link	c.782A>T	p.Gln261Leu	missense_variant	Exon 4 of 4	ENST00000302277.7	NP_919226.1	Q7Z570

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF804A	ENST00000302277.7 link	c.782A>T	p.Gln261Leu	missense_variant	Exon 4 of 4	1	NM_194250.2	ENSP00000303252.6		Q7Z570

Frequencies

GnomAD3 genomes

AF:

0.599

AC:

90997

AN:

151928

Hom.:

27995

Cov.:

show subpopulations

Gnomad AFR

AF:

0.465

Gnomad AMI

AF:

0.465

Gnomad AMR

AF:

0.710

Gnomad ASJ

AF:

0.704

Gnomad EAS

AF:

0.831

Gnomad SAS

AF:

0.616

Gnomad FIN

AF:

0.652

Gnomad MID

AF:

0.595

Gnomad NFE

AF:

0.624

Gnomad OTH

AF:

0.619

GnomAD2 exomes

AF:

0.656

AC:

164749

AN:

251092

AF XY:

0.653

show subpopulations

Gnomad AFR exome

AF:

0.465

Gnomad AMR exome

AF:

0.756

Gnomad ASJ exome

AF:

0.704

Gnomad EAS exome

AF:

0.842

Gnomad FIN exome

AF:

0.668

Gnomad NFE exome

AF:

0.625

Gnomad OTH exome

AF:

0.657

GnomAD4 exome

AF:

0.632

AC:

924106

AN:

1461704

Hom.:

294493

Cov.:

AF XY:

0.632

AC XY:

459796

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.457

AC:

15296

AN:

33474

American (AMR)

AF:

0.750

AC:

33528

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.695

AC:

18168

AN:

26134

East Asian (EAS)

AF:

0.850

AC:

33734

AN:

39686

South Asian (SAS)

AF:

0.628

AC:

54183

AN:

86250

European-Finnish (FIN)

AF:

0.663

AC:

35427

AN:

53408

Middle Eastern (MID)

AF:

0.570

AC:

3285

AN:

5766

European-Non Finnish (NFE)

AF:

0.623

AC:

692673

AN:

1111892

Other (OTH)

AF:

0.626

AC:

37812

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

20353

40706

61059

81412

101765

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18622

37244

55866

74488

93110

<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:

0.599

AC:

91041

AN:

152046

Hom.:

28002

Cov.:

AF XY:

0.603

AC XY:

44784

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.465

AC:

19269

AN:

41448

American (AMR)

AF:

0.710

AC:

10834

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.704

AC:

2446

AN:

3472

East Asian (EAS)

AF:

0.831

AC:

4294

AN:

5168

South Asian (SAS)

AF:

0.619

AC:

2984

AN:

4824

European-Finnish (FIN)

AF:

0.652

AC:

6890

AN:

10572

Middle Eastern (MID)

AF:

0.595

AC:

175

AN:

294

European-Non Finnish (NFE)

AF:

0.624

AC:

42432

AN:

67976

Other (OTH)

AF:

0.612

AC:

1294

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1821

3641

5462

7282

9103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

762

1524

2286

3048

3810

<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:

0.629

Hom.:

22845

Bravo

AF:

0.601

TwinsUK

AF:

0.622

AC:

2307

ALSPAC

AF:

0.642

AC:

2474

ESP6500AA

AF:

0.479

AC:

2109

ESP6500EA

AF:

0.629

AC:

5404

ExAC

AF:

0.645

AC:

78267

Asia WGS

AF:

0.666

AC:

2316

AN:

3478

EpiCase

AF:

0.624

EpiControl

AF:

0.634

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 14, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24315717) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.27

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.0039

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0036

LIST_S2

Benign

0.024

T;T

MetaRNN

Benign

0.0000011

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.8

N;.

PhyloP100

-0.15

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.73

N;.

REVEL

Benign

0.062

Sift

Benign

0.37

T;.

Sift4G

Benign

0.31

T;T

Polyphen

0.0

B;.

Vest4

0.018

MPC

0.035

ClinPred

0.0039

GERP RS

0.19

Varity_R

0.062

gMVP

0.066

Mutation Taster

=100/0

polymorphism (auto)

(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