Genetic Variant NM_181646.5:c.743G>A (chr7-89333725-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_181646.5(ZNF804B):c.743G>A(p.Cys248Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0347 in 1,613,456 control chromosomes in the GnomAD database, including 7,354 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.041 ( 754 hom., cov: 32)

Exomes 𝑓: 0.034 ( 6600 hom. )

Consequence

ZNF804B
NM_181646.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.79

Publications

12 publications found

Variant links:

Genes affected

ZNF804B (HGNC:21958): (zinc finger protein 804B) Predicted to enable metal ion binding activity. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF804B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.710853E-4).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF804B	NM_181646.5 link	c.743G>A	p.Cys248Tyr	missense_variant	Exon 4 of 4	ENST00000333190.5	NP_857597.1	A4D1E1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF804B	ENST00000333190.5 link	c.743G>A	p.Cys248Tyr	missense_variant	Exon 4 of 4	1	NM_181646.5	ENSP00000329638.4		A4D1E1
ZNF804B	ENST00000611114.1 link	c.494G>A	p.Cys165Tyr	missense_variant	Exon 3 of 3	5		ENSP00000478506.1		A0A087WUA7

Frequencies

GnomAD3 genomes

AF:

0.0415

AC:

6305

AN:

151964

Hom.:

753

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0191

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.111

Gnomad ASJ

AF:

0.0110

Gnomad EAS

AF:

0.463

Gnomad SAS

AF:

0.156

Gnomad FIN

AF:

0.0132

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00603

Gnomad OTH

AF:

0.0431

GnomAD2 exomes

AF:

0.0882

AC:

22034

AN:

249928

AF XY:

0.0817

show subpopulations

Gnomad AFR exome

AF:

0.0200

Gnomad AMR exome

AF:

0.228

Gnomad ASJ exome

AF:

0.0128

Gnomad EAS exome

AF:

0.457

Gnomad FIN exome

AF:

0.0117

Gnomad NFE exome

AF:

0.00560

Gnomad OTH exome

AF:

0.0567

GnomAD4 exome

AF:

0.0340

AC:

49700

AN:

1461374

Hom.:

6600

Cov.:

AF XY:

0.0358

AC XY:

26036

AN XY:

726980

show subpopulations

African (AFR)

AF:

0.0189

AC:

632

AN:

33450

American (AMR)

AF:

0.212

AC:

9470

AN:

44626

Ashkenazi Jewish (ASJ)

AF:

0.0120

AC:

314

AN:

26110

East Asian (EAS)

AF:

0.455

AC:

18057

AN:

39688

South Asian (SAS)

AF:

0.133

AC:

11492

AN:

86238

European-Finnish (FIN)

AF:

0.0112

AC:

596

AN:

53366

Middle Eastern (MID)

AF:

0.0118

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00549

AC:

6104

AN:

1111758

Other (OTH)

AF:

0.0491

AC:

2967

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

2417

4833

7250

9666

12083

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

688

1376

2064

2752

3440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0415

AC:

6309

AN:

152082

Hom.:

754

Cov.:

AF XY:

0.0466

AC XY:

3465

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.0191

AC:

794

AN:

41532

American (AMR)

AF:

0.112

AC:

1704

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.0110

AC:

AN:

3466

East Asian (EAS)

AF:

0.463

AC:

2380

AN:

5136

South Asian (SAS)

AF:

0.154

AC:

743

AN:

4822

European-Finnish (FIN)

AF:

0.0132

AC:

140

AN:

10588

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00603

AC:

410

AN:

67974

Other (OTH)

AF:

0.0451

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

239

478

718

957

1196

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

246

328

410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0271

Hom.:

2227

Bravo

AF:

0.0510

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.0184

AC:

ESP6500EA

AF:

0.00628

AC:

ExAC

AF:

0.0817

AC:

9918

Asia WGS

AF:

0.300

AC:

1040

AN:

3478

EpiCase

AF:

0.00551

EpiControl

AF:

0.00481

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.32

DEOGEN2

Benign

0.018

T;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.74

T;T

MetaRNN

Benign

0.00047

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.2

M;.

PhyloP100

2.8

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.0

D;.

REVEL

Benign

0.057

Sift

Benign

0.16

T;.

Sift4G

Benign

1.0

T;T

Polyphen

0.22

B;.

Vest4

0.055

MPC

0.058

ClinPred

0.030

GERP RS

4.2

Varity_R

0.12

gMVP

0.11

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over