rs3731834

Variant names:

• chr2-184938637-C-G
• rs3731834
• NM_194250.2:c.3241C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_194250.2(ZNF804A):​c.3241C>G​(p.Leu1081Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,613,834 control chromosomes in the GnomAD database, including 25,456 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 0.14 (1786 hom., cov: 31)
  • Exomes 𝑓: 0.17 (23670 hom.)
• Consequence: ZNF804A NM_194250.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.14
• Publications: 25 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030513406).
• BP6: Variant 2-184938637-C-G is Benign according to our data. Variant chr2-184938637-C-G is described in ClinVar as Benign. ClinVar VariationId is 1280392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.25 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.3241C>G	p.Leu1081Val	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.3241C>G	p.Leu1081Val	missense	Exon 4 of 4	ENSP00000303252.6	Q7Z570

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21422 AN: 151974 Hom.: 1789 Cov.: 31

Gnomad AFR AF: 0.0629

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.207

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.169

GnomAD2 exomes AF: 0.172 AC: 43052 AN: 250864 AF XY: 0.183

Gnomad AFR exome AF: 0.0601

Gnomad AMR exome AF: 0.0977

Gnomad ASJ exome AF: 0.205

Gnomad EAS exome AF: 0.205

Gnomad FIN exome AF: 0.151

Gnomad NFE exome AF: 0.176

Gnomad OTH exome AF: 0.185

GnomAD4 exome AF: 0.175 AC: 255542 AN: 1461742 Hom.: 23670 Cov.: 38 AF XY: 0.180 AC XY: 130885 AN XY: 727168

African (AFR) AF: 0.0591 AC: 1980 AN: 33480

American (AMR) AF: 0.102 AC: 4547 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 5327 AN: 26130

East Asian (EAS) AF: 0.225 AC: 8925 AN: 39698

South Asian (SAS) AF: 0.275 AC: 23741 AN: 86254

European-Finnish (FIN) AF: 0.153 AC: 8179 AN: 53398

Middle Eastern (MID) AF: 0.243 AC: 1404 AN: 5766

European-Non Finnish (NFE) AF: 0.172 AC: 190819 AN: 1111910

Other (OTH) AF: 0.176 AC: 10620 AN: 60396

GnomAD4 genome AF: 0.141 AC: 21407 AN: 152092 Hom.: 1786 Cov.: 31 AF XY: 0.140 AC XY: 10439 AN XY: 74334

African (AFR) AF: 0.0627 AC: 2605 AN: 41520

American (AMR) AF: 0.124 AC: 1899 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 757 AN: 3466

East Asian (EAS) AF: 0.202 AC: 1041 AN: 5142

South Asian (SAS) AF: 0.262 AC: 1263 AN: 4812

European-Finnish (FIN) AF: 0.137 AC: 1449 AN: 10586

Middle Eastern (MID) AF: 0.209 AC: 61 AN: 292

European-Non Finnish (NFE) AF: 0.175 AC: 11883 AN: 67964

Other (OTH) AF: 0.166 AC: 350 AN: 2112

Alfa AF: 0.168 Hom.: 686

Bravo AF: 0.134

TwinsUK AF: 0.159 AC: 590

ALSPAC AF: 0.174 AC: 669

ESP6500AA AF: 0.0672 AC: 296

ESP6500EA AF: 0.176 AC: 1517

ExAC AF: 0.173 AC: 20998

Asia WGS AF: 0.207 AC: 717 AN: 3478

EpiCase AF: 0.185

EpiControl AF: 0.185

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	ZNF804A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	13
DANN	Benign	0.76
DEOGEN2	Benign	0.0085	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.52
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.1
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.045
Sift	Benign	0.55	T
Sift4G	Benign	0.34	T
Polyphen		0.19	B
Vest4		0.043
MPC		0.25
ClinPred		0.0046	T
GERP RS		3.2
Varity_R		0.038
gMVP		0.24
Mutation Taster		=98/2	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: rs3731834; hg19: chr2-185803364; COSMIC: COSV56438838;