2-184936832-A-G

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF804A	NM_194250.2	c.1436A>G	p.Asp479Gly	missense_variant	Exon 4 of 4	ENST00000302277.7	NP_919226.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF804A	ENST00000302277.7	c.1436A>G	p.Asp479Gly	missense_variant	Exon 4 of 4	1	NM_194250.2	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

GnomAD3 exomes AF: 0.0538 AC: 13394 AN: 248910 Hom.: 454 AF XY: 0.0557 AC XY: 7515 AN XY: 134868

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 SAS exome AF: 0.0408

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

Gnomad4 AFR exome AF: 0.0249

Gnomad4 AMR exome AF: 0.0327

Gnomad4 ASJ exome AF: 0.0782

Gnomad4 EAS exome AF: 0.0225

Gnomad4 SAS exome AF: 0.0422

Gnomad4 FIN exome AF: 0.0399

Gnomad4 NFE exome AF: 0.0747

Gnomad4 OTH exome AF: 0.0643

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

Gnomad4 AFR AF: 0.0269

Gnomad4 AMR AF: 0.0515

Gnomad4 ASJ AF: 0.0801

Gnomad4 EAS AF: 0.0226

Gnomad4 SAS AF: 0.0470

Gnomad4 FIN AF: 0.0368

Gnomad4 NFE AF: 0.0744

Gnomad4 OTH AF: 0.0545

Alfa AF: 0.0700 Hom.: 653

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 v4.3

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;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.61	T;T
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.3	N;.
REVEL	Benign	0.030
Sift	Benign	0.36	T;.
Sift4G	Benign	0.38	T;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

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: rs35676856; hg19: chr2-185801559; COSMIC: COSV56473132;