Genetic Variant NM_194250.2:c.980A>C (chr2-184936376-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_194250.2(ZNF804A):c.980A>C(p.Asn327Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0269 in 1,614,010 control chromosomes in the GnomAD database, including 691 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.019 ( 49 hom., cov: 33)

Exomes 𝑓: 0.028 ( 642 hom. )

Consequence

ZNF804A
NM_194250.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0790

Publications

9 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002303481).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.019 (2887/152312) while in subpopulation NFE AF = 0.0287 (1949/68010). AF 95% confidence interval is 0.0276. There are 49 homozygotes in GnomAd4. There are 1352 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 2887 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194250.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF804A	NM_194250.2	MANE Select	c.980A>C	p.Asn327Thr	missense	Exon 4 of 4	NP_919226.1	Q7Z570

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF804A	ENST00000302277.7	TSL:1 MANE Select	c.980A>C	p.Asn327Thr	missense	Exon 4 of 4	ENSP00000303252.6	Q7Z570

Frequencies

GnomAD3 genomes

AF:

0.0190

AC:

2886

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00596

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0107

Gnomad ASJ

AF:

0.0222

Gnomad EAS

AF:

0.000769

Gnomad SAS

AF:

0.0178

Gnomad FIN

AF:

0.0299

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0287

Gnomad OTH

AF:

0.0143

GnomAD2 exomes

AF:

0.0196

AC:

4889

AN:

249558

AF XY:

0.0201

show subpopulations

Gnomad AFR exome

AF:

0.00460

Gnomad AMR exome

AF:

0.00748

Gnomad ASJ exome

AF:

0.0221

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.0276

Gnomad NFE exome

AF:

0.0273

Gnomad OTH exome

AF:

0.0205

GnomAD4 exome

AF:

0.0277

AC:

40454

AN:

1461698

Hom.:

642

Cov.:

AF XY:

0.0273

AC XY:

19841

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.00394

AC:

132

AN:

33478

American (AMR)

AF:

0.00799

AC:

357

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.0212

AC:

553

AN:

26132

East Asian (EAS)

AF:

0.000101

AC:

AN:

39662

South Asian (SAS)

AF:

0.0190

AC:

1635

AN:

86252

European-Finnish (FIN)

AF:

0.0272

AC:

1454

AN:

53408

Middle Eastern (MID)

AF:

0.00937

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0313

AC:

34786

AN:

1111938

Other (OTH)

AF:

0.0245

AC:

1479

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

2269

4537

6806

9074

11343

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1292

2584

3876

5168

6460

<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:

0.0190

AC:

2887

AN:

152312

Hom.:

Cov.:

AF XY:

0.0182

AC XY:

1352

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00594

AC:

247

AN:

41588

American (AMR)

AF:

0.0107

AC:

163

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

AN:

3470

East Asian (EAS)

AF:

0.000771

AC:

AN:

5188

South Asian (SAS)

AF:

0.0180

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0299

AC:

317

AN:

10616

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0287

AC:

1949

AN:

68010

Other (OTH)

AF:

0.0142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

150

300

449

599

749

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0257

Hom.:

168

Bravo

AF:

0.0174

TwinsUK

AF:

0.0305

AC:

113

ALSPAC

AF:

0.0371

AC:

143

ESP6500AA

AF:

0.00681

AC:

ESP6500EA

AF:

0.0271

AC:

233

ExAC

AF:

0.0194

AC:

2353

Asia WGS

AF:

0.00693

AC:

AN:

3478

EpiCase

AF:

0.0242

EpiControl

AF:

0.0264

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.71

CADD

Benign

1.1

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0051

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PhyloP100

0.079

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.1

REVEL

Benign

0.022

Sift

Benign

0.30

Sift4G

Benign

0.22

Polyphen

0.14

Vest4

0.032

MPC

0.050

ClinPred

0.0053

GERP RS

3.1

Varity_R

0.065

gMVP

0.072

Mutation Taster

=97/3

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over