rs1366842

chr2-184937516-C-Achr2-184937516-C-Gchr2-184937516-C-T

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.2120C>A(p.Thr707Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.571 in 1,607,472 control chromosomes in the GnomAD database, including 273,663 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.47 (20719 hom., cov: 33)
  • Exomes 𝑓: 0.58 (252944 hom.)
• Consequence: ZNF804A NM_194250.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.183

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=8.356307E-7).
• BP6: Variant 2-184937516-C-A is Benign according to our data. Variant chr2-184937516-C-A is described in ClinVar as [Benign]. Clinvar id is 3059400.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.812 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF804A	NM_194250.2	c.2120C>A	p.Thr707Lys	missense_variant	4/4	ENST00000302277.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF804A	ENST00000302277.7	c.2120C>A	p.Thr707Lys	missense_variant	4/4	1	NM_194250.2	P1

Frequencies

GnomAD3 genomes AF: 0.474 AC: 72074 AN: 151958 Hom.: 20721 Cov.: 33

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.465

Gnomad AMR AF: 0.644

Gnomad ASJ AF: 0.608

Gnomad EAS AF: 0.833

Gnomad SAS AF: 0.540

Gnomad FIN AF: 0.629

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.580

Gnomad OTH AF: 0.501

GnomAD3 exomes AF: 0.593 AC: 144400 AN: 243692 Hom.: 45977 AF XY: 0.591 AC XY: 78077 AN XY: 132160

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.716

Gnomad ASJ exome AF: 0.615

Gnomad EAS exome AF: 0.847

Gnomad SAS exome AF: 0.541

Gnomad FIN exome AF: 0.645

Gnomad NFE exome AF: 0.582

Gnomad OTH exome AF: 0.591

GnomAD4 exome AF: 0.581 AC: 846302 AN: 1455396 Hom.: 252944 Cov.: 43 AF XY: 0.581 AC XY: 420564 AN XY: 723870

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.707

Gnomad4 ASJ exome AF: 0.609

Gnomad4 EAS exome AF: 0.844

Gnomad4 SAS exome AF: 0.547

Gnomad4 FIN exome AF: 0.640

Gnomad4 NFE exome AF: 0.583

Gnomad4 OTH exome AF: 0.560

GnomAD4 genome AF: 0.474 AC: 72073 AN: 152076 Hom.: 20719 Cov.: 33 AF XY: 0.480 AC XY: 35700 AN XY: 74350

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.644

Gnomad4 ASJ AF: 0.608

Gnomad4 EAS AF: 0.833

Gnomad4 SAS AF: 0.542

Gnomad4 FIN AF: 0.629

Gnomad4 NFE AF: 0.580

Gnomad4 OTH AF: 0.497

Alfa AF: 0.573 Hom.: 38880

Bravo AF: 0.465

TwinsUK AF: 0.586 AC: 2172

ALSPAC AF: 0.603 AC: 2323

ESP6500AA AF: 0.140 AC: 615

ESP6500EA AF: 0.577 AC: 4953

ExAC AF: 0.575 AC: 69820

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

Oct 17, 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	0.092
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.84
Cadd	Benign	4.9
Dann	Benign	0.15
DEOGEN2	Benign	0.0039	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.44	T;T
MetaRNN	Benign	8.4e-7	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.21	N;.
REVEL	Benign	0.018
Sift	Benign	1.0	T;.
Sift4G	Benign	0.97	T;T
Polyphen		0.0020	B;.
Vest4		0.026
MPC		0.28
ClinPred		0.0059	T
GERP RS		1.9
Varity_R		0.022
gMVP		0.11

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: rs1366842; hg19: chr2-185802243; COSMIC: COSV56451912;