rs12477430

Variant names:

• chr2-184937636-A-G
• rs12477430
• NM_194250.2:c.2240A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_194250.2(ZNF804A):​c.2240A>G​(p.His747Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.704 in 1,613,410 control chromosomes in the GnomAD database, including 401,719 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H747Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.69 (36812 hom., cov: 33)
  • Exomes 𝑓: 0.71 (364907 hom.)
• Consequence: ZNF804A NM_194250.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0660
• Publications: 33 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.7846036E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.845 is higher than 0.05.

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.2240A>G	p.His747Arg	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.2240A>G	p.His747Arg	missense	Exon 4 of 4	ENSP00000303252.6	Q7Z570

Frequencies

GnomAD3 genomes AF: 0.693 AC: 105368 AN: 151948 Hom.: 36799 Cov.: 33

Gnomad AFR AF: 0.630

Gnomad AMI AF: 0.519

Gnomad AMR AF: 0.779

Gnomad ASJ AF: 0.790

Gnomad EAS AF: 0.866

Gnomad SAS AF: 0.668

Gnomad FIN AF: 0.687

Gnomad MID AF: 0.693

Gnomad NFE AF: 0.699

Gnomad OTH AF: 0.714

GnomAD2 exomes AF: 0.722 AC: 180563 AN: 250068 AF XY: 0.718

Gnomad AFR exome AF: 0.630

Gnomad AMR exome AF: 0.797

Gnomad ASJ exome AF: 0.791

Gnomad EAS exome AF: 0.866

Gnomad FIN exome AF: 0.704

Gnomad NFE exome AF: 0.701

Gnomad OTH exome AF: 0.725

GnomAD4 exome AF: 0.705 AC: 1030490 AN: 1461344 Hom.: 364907 Cov.: 53 AF XY: 0.704 AC XY: 512040 AN XY: 726954

African (AFR) AF: 0.628 AC: 21031 AN: 33476

American (AMR) AF: 0.793 AC: 35415 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 20441 AN: 26126

East Asian (EAS) AF: 0.889 AC: 35258 AN: 39662

South Asian (SAS) AF: 0.673 AC: 58017 AN: 86224

European-Finnish (FIN) AF: 0.703 AC: 37498 AN: 53328

Middle Eastern (MID) AF: 0.667 AC: 3845 AN: 5764

European-Non Finnish (NFE) AF: 0.699 AC: 776603 AN: 1111738

Other (OTH) AF: 0.702 AC: 42382 AN: 60386

GnomAD4 genome AF: 0.693 AC: 105421 AN: 152066 Hom.: 36812 Cov.: 33 AF XY: 0.694 AC XY: 51600 AN XY: 74324

African (AFR) AF: 0.630 AC: 26112 AN: 41458

American (AMR) AF: 0.778 AC: 11888 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.790 AC: 2741 AN: 3470

East Asian (EAS) AF: 0.866 AC: 4476 AN: 5170

South Asian (SAS) AF: 0.669 AC: 3231 AN: 4826

European-Finnish (FIN) AF: 0.687 AC: 7268 AN: 10584

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.699 AC: 47541 AN: 67966

Other (OTH) AF: 0.705 AC: 1488 AN: 2110

Alfa AF: 0.705 Hom.: 126365

Bravo AF: 0.700

TwinsUK AF: 0.702 AC: 2602

ALSPAC AF: 0.714 AC: 2753

ESP6500AA AF: 0.637 AC: 2807

ESP6500EA AF: 0.709 AC: 6096

ExAC AF: 0.713 AC: 86553

Asia WGS AF: 0.717 AC: 2493 AN: 3478

EpiCase AF: 0.705

EpiControl AF: 0.716

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.39
DANN	Benign	0.76
DEOGEN2	Benign	0.0051	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0010	N
LIST_S2	Benign	0.051	T
MetaRNN	Benign	8.8e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N
PhyloP100		0.066
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.063
Sift	Benign	0.40	T
Sift4G	Benign	0.37	T
Polyphen		0.0	B
Vest4		0.0070
MPC		0.040
ClinPred		0.017	T
GERP RS		2.0
Varity_R		0.019
gMVP		0.019
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12477430; hg19: chr2-185802363; COSMIC: COSV56451920;