chr2-184937020-G-A

Variant names:

• chr2-184937020-G-A
• rs4667001
• NM_194250.2:c.1624G>A

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.1624G>A​(p.Glu542Lys) 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 1,612,128 control chromosomes in the GnomAD database, including 274,003 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 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 0.47 (20580 hom., cov: 31)
  • Exomes 𝑓: 0.58 (253423 hom.)
• Consequence: ZNF804A NM_194250.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.56

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0094146E-6).
• BP6: Variant 2-184937020-G-A is Benign according to our data. Variant chr2-184937020-G-A is described in ClinVar as [Benign]. Clinvar id is 3059275.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.81 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF804A	NM_194250.2	c.1624G>A	p.Glu542Lys	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.1624G>A	p.Glu542Lys	missense_variant	Exon 4 of 4	1	NM_194250.2	ENSP00000303252.6

Frequencies

GnomAD3 genomes AF: 0.473 AC: 71764 AN: 151584 Hom.: 20583 Cov.: 31

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.462

Gnomad AMR AF: 0.643

Gnomad ASJ AF: 0.606

Gnomad EAS AF: 0.831

Gnomad SAS AF: 0.540

Gnomad FIN AF: 0.626

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.579

Gnomad OTH AF: 0.501

GnomAD2 exomes AF: 0.594 AC: 147519 AN: 248450 AF XY: 0.591

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.717

Gnomad ASJ exome AF: 0.616

Gnomad EAS exome AF: 0.846

Gnomad FIN exome AF: 0.645

Gnomad NFE exome AF: 0.583

Gnomad OTH exome AF: 0.594

GnomAD4 exome AF: 0.582 AC: 849304 AN: 1460426 Hom.: 253423 Cov.: 48 AF XY: 0.581 AC XY: 422100 AN XY: 726474

Gnomad4 AFR exome AF: 0.113 AC: 3771 AN: 33436

Gnomad4 AMR exome AF: 0.708 AC: 31492 AN: 44476

Gnomad4 ASJ exome AF: 0.610 AC: 15901 AN: 26062

Gnomad4 EAS exome AF: 0.844 AC: 33426 AN: 39602

Gnomad4 SAS exome AF: 0.548 AC: 47173 AN: 86144

Gnomad4 FIN exome AF: 0.641 AC: 34182 AN: 53366

Gnomad4 NFE exome AF: 0.582 AC: 647194 AN: 1111276

Gnomad4 Remaining exome AF: 0.560 AC: 33773 AN: 60310

GnomAD4 genome AF: 0.473 AC: 71762 AN: 151702 Hom.: 20580 Cov.: 31 AF XY: 0.479 AC XY: 35497 AN XY: 74104

Gnomad4 AFR AF: 0.133 AC: 0.133147 AN: 0.133147

Gnomad4 AMR AF: 0.643 AC: 0.643241 AN: 0.643241

Gnomad4 ASJ AF: 0.606 AC: 0.605719 AN: 0.605719

Gnomad4 EAS AF: 0.831 AC: 0.831131 AN: 0.831131

Gnomad4 SAS AF: 0.543 AC: 0.542584 AN: 0.542584

Gnomad4 FIN AF: 0.626 AC: 0.626478 AN: 0.626478

Gnomad4 NFE AF: 0.579 AC: 0.579355 AN: 0.579355

Gnomad4 OTH AF: 0.497 AC: 0.496676 AN: 0.496676

Alfa AF: 0.533 Hom.: 42929

Bravo AF: 0.465

TwinsUK AF: 0.586 AC: 2172

ALSPAC AF: 0.603 AC: 2323

ESP6500AA AF: 0.140 AC: 603

ESP6500EA AF: 0.577 AC: 4940

ExAC AF: 0.576 AC: 69820

Asia WGS AF: 0.615 AC: 2136 AN: 3474

EpiCase AF: 0.577

EpiControl AF: 0.584

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ZNF804A-related disorder Benign:1

Oct 17, 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	0.068
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0072	T;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.67	T;T
MetaRNN	Benign	0.0000010	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.038
Sift	Benign	0.11	T;.
Sift4G	Benign	0.22	T;T
Polyphen		0.012	B;.
Vest4		0.025
MPC		0.039
ClinPred		0.0025	T
GERP RS		3.2
Varity_R		0.093
gMVP		0.11
Mutation Taster		=97/3	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

Publications

LitVar

Other links and lift over

dbSNP: rs4667001; hg19: chr2-185801747; COSMIC: COSV104534934;