2-184936832-A-G

Variant names:

• chr2-184936832-A-G
• rs35676856
• NM_194250.2:c.1436A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_194250.2(ZNF804A):​c.1436A>G​(p.Asp479Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0661 in 1,612,436 control chromosomes in the GnomAD database, including 3,833 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.054 (266 hom., cov: 32)
  • Exomes 𝑓: 0.067 (3567 hom.)
• Consequence: ZNF804A NM_194250.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.452
• Publications: 12 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032455027).
• BP6: Variant 2-184936832-A-G is Benign according to our data. Variant chr2-184936832-A-G is described in ClinVar as Benign. ClinVar VariationId is 3055649.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0727 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF804A	NM_194250.2	MANE Select	c.1436A>G	p.Asp479Gly	missense	Exon 4 of 4	NP_919226.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF804A	ENST00000302277.7	TSL:1 MANE Select	c.1436A>G	p.Asp479Gly	missense	Exon 4 of 4	ENSP00000303252.6

Frequencies

GnomAD3 genomes AF: 0.0537 AC: 8169 AN: 152142 Hom.: 266 Cov.: 32

Gnomad AFR AF: 0.0269

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0516

Gnomad ASJ AF: 0.0801

Gnomad EAS AF: 0.0227

Gnomad SAS AF: 0.0474

Gnomad FIN AF: 0.0368

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0744

Gnomad OTH AF: 0.0555

GnomAD2 exomes AF: 0.0538 AC: 13394 AN: 248910 AF XY: 0.0557

Gnomad AFR exome AF: 0.0269

Gnomad AMR exome AF: 0.0310

Gnomad ASJ exome AF: 0.0797

Gnomad EAS exome AF: 0.0165

Gnomad FIN exome AF: 0.0364

Gnomad NFE exome AF: 0.0748

Gnomad OTH exome AF: 0.0604

GnomAD4 exome AF: 0.0673 AC: 98340 AN: 1460176 Hom.: 3567 Cov.: 56 AF XY: 0.0669 AC XY: 48624 AN XY: 726462

African (AFR) AF: 0.0249 AC: 830 AN: 33318

American (AMR) AF: 0.0327 AC: 1448 AN: 44312

Ashkenazi Jewish (ASJ) AF: 0.0782 AC: 2033 AN: 26002

East Asian (EAS) AF: 0.0225 AC: 892 AN: 39664

South Asian (SAS) AF: 0.0422 AC: 3630 AN: 86112

European-Finnish (FIN) AF: 0.0399 AC: 2131 AN: 53390

Middle Eastern (MID) AF: 0.0816 AC: 468 AN: 5736

European-Non Finnish (NFE) AF: 0.0747 AC: 83034 AN: 1111372

Other (OTH) AF: 0.0643 AC: 3874 AN: 60270

GnomAD4 genome AF: 0.0536 AC: 8163 AN: 152260 Hom.: 266 Cov.: 32 AF XY: 0.0517 AC XY: 3846 AN XY: 74442

African (AFR) AF: 0.0269 AC: 1116 AN: 41548

American (AMR) AF: 0.0515 AC: 787 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0801 AC: 278 AN: 3470

East Asian (EAS) AF: 0.0226 AC: 117 AN: 5178

South Asian (SAS) AF: 0.0470 AC: 227 AN: 4832

European-Finnish (FIN) AF: 0.0368 AC: 391 AN: 10612

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0744 AC: 5060 AN: 68016

Other (OTH) AF: 0.0545 AC: 115 AN: 2112

Alfa AF: 0.0683 Hom.: 1265

Bravo AF: 0.0536

TwinsUK AF: 0.0779 AC: 289

ALSPAC AF: 0.0708 AC: 273

ESP6500AA AF: 0.0261 AC: 115

ESP6500EA AF: 0.0778 AC: 669

ExAC AF: 0.0543 AC: 6594

Asia WGS AF: 0.0380 AC: 133 AN: 3478

EpiCase AF: 0.0792

EpiControl AF: 0.0798

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ZNF804A-related disorder Benign:1

Dec 09, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.0
DANN	Benign	0.83
DEOGEN2	Benign	0.0043	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.45
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.030
Sift	Benign	0.36	T
Sift4G	Benign	0.38	T
Polyphen		0.0010	B
Vest4		0.053
MPC		0.042
ClinPred		0.0036	T
GERP RS		1.5
Varity_R		0.039
gMVP		0.14
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: rs35676856; hg19: chr2-185801559; COSMIC: COSV56473132;