2-184936370-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_194250.2(ZNF804A):c.974G>T(p.Cys325Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0004 in 1,613,972 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00032 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (4 hom.)
• Consequence: ZNF804A NM_194250.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.32

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006750345).
• BP6: Variant 2-184936370-G-T is Benign according to our data. Variant chr2-184936370-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 3041236.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF804A	NM_194250.2	c.974G>T	p.Cys325Phe	missense_variant	4/4	ENST00000302277.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF804A	ENST00000302277.7	c.974G>T	p.Cys325Phe	missense_variant	4/4	1	NM_194250.2	P1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152160 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000798 AC: 199 AN: 249496 Hom.: 3 AF XY: 0.000719 AC XY: 97 AN XY: 134988

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00608

Gnomad EAS exome AF: 0.00393

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000329

Gnomad OTH exome AF: 0.000987

GnomAD4 exome AF: 0.000408 AC: 596 AN: 1461692 Hom.: 4 Cov.: 56 AF XY: 0.000422 AC XY: 307 AN XY: 727132

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00540

Gnomad4 EAS exome AF: 0.00560

Gnomad4 SAS exome AF: 0.000568

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000118

Gnomad4 OTH exome AF: 0.000729

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152280 Hom.: 1 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74470

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00577

Gnomad4 EAS AF: 0.00367

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000631 Hom.: 1

Bravo AF: 0.000434

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000692 AC: 84

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ZNF804A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2019

This variant is classified as likely 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	0.093
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0068	T;T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0068	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.0	N;.
REVEL	Benign	0.12
Sift	Benign	0.17	T;.
Sift4G	Benign	0.71	T;T
Polyphen		0.90	P;.
Vest4		0.51
MVP		0.082
MPC		0.31
ClinPred		0.048	T
GERP RS		4.6
Varity_R		0.11
gMVP		0.28

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: rs139826553; hg19: chr2-185801097;