rs61739290

chr2-184936870-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_194250.2(ZNF804A):c.1474A>G(p.Ile492Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.066 in 1,613,082 control chromosomes in the GnomAD database, including 3,839 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.054 (266 hom., cov: 32)
  • Exomes 𝑓: 0.067 (3573 hom.)
• Consequence: ZNF804A NM_194250.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0610

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024322867).
• BP6: Variant 2-184936870-A-G is Benign according to our data. Variant chr2-184936870-A-G is described in ClinVar as [Benign]. Clinvar id is 3055535.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF804A	NM_194250.2	c.1474A>G	p.Ile492Val	missense_variant	4/4	ENST00000302277.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF804A	ENST00000302277.7	c.1474A>G	p.Ile492Val	missense_variant	4/4	1	NM_194250.2	P1

Frequencies

GnomAD3 genomes AF: 0.0536 AC: 8160 AN: 152148 Hom.: 266 Cov.: 32

Gnomad AFR AF: 0.0269

Gnomad AMI AF: 0.0527

Gnomad AMR AF: 0.0513

Gnomad ASJ AF: 0.0801

Gnomad EAS AF: 0.0227

Gnomad SAS AF: 0.0472

Gnomad FIN AF: 0.0365

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0744

Gnomad OTH AF: 0.0559

GnomAD3 exomes AF: 0.0537 AC: 13412 AN: 249618 Hom.: 455 AF XY: 0.0557 AC XY: 7532 AN XY: 135232

Gnomad AFR exome AF: 0.0267

Gnomad AMR exome AF: 0.0310

Gnomad ASJ exome AF: 0.0793

Gnomad EAS exome AF: 0.0166

Gnomad SAS exome AF: 0.0408

Gnomad FIN exome AF: 0.0364

Gnomad NFE exome AF: 0.0747

Gnomad OTH exome AF: 0.0603

GnomAD4 exome AF: 0.0673 AC: 98334 AN: 1460816 Hom.: 3573 Cov.: 58 AF XY: 0.0669 AC XY: 48616 AN XY: 726684

Gnomad4 AFR exome AF: 0.0249

Gnomad4 AMR exome AF: 0.0326

Gnomad4 ASJ exome AF: 0.0781

Gnomad4 EAS exome AF: 0.0225

Gnomad4 SAS exome AF: 0.0421

Gnomad4 FIN exome AF: 0.0399

Gnomad4 NFE exome AF: 0.0747

Gnomad4 OTH exome AF: 0.0643

GnomAD4 genome AF: 0.0536 AC: 8154 AN: 152266 Hom.: 266 Cov.: 32 AF XY: 0.0516 AC XY: 3839 AN XY: 74452

Gnomad4 AFR AF: 0.0268

Gnomad4 AMR AF: 0.0512

Gnomad4 ASJ AF: 0.0801

Gnomad4 EAS AF: 0.0226

Gnomad4 SAS AF: 0.0468

Gnomad4 FIN AF: 0.0365

Gnomad4 NFE AF: 0.0744

Gnomad4 OTH AF: 0.0548

Alfa AF: 0.0705 Hom.: 651

Bravo AF: 0.0537

TwinsUK AF: 0.0779 AC: 289

ALSPAC AF: 0.0708 AC: 273

ESP6500AA AF: 0.0259 AC: 114

ESP6500EA AF: 0.0778 AC: 669

ExAC AF: 0.0543 AC: 6595

Asia WGS AF: 0.0380 AC: 133 AN: 3478

EpiCase AF: 0.0792

EpiControl AF: 0.0797

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ZNF804A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 09, 2019

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.094
Dann	Benign	0.14
DEOGEN2	Benign	0.0038	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.53	T;T
MetaRNN	Benign	0.0024	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.11	N;.
REVEL	Benign	0.040
Sift	Benign	0.24	T;.
Sift4G	Benign	0.50	T;T
Polyphen		0.0010	B;.
Vest4		0.015
MPC		0.20
ClinPred		0.0076	T
GERP RS		-5.0
Varity_R		0.025
gMVP		0.052

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

LitVar

Other links and lift over

dbSNP: rs61739290; hg19: chr2-185801597; COSMIC: COSV56473145;