Genetic Variant ZNF669:p.Val375Leu (chr1-247100388-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001142572.2(ZNF669):c.1123G>C(p.Val375Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,598,924 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V375M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0067 ( 15 hom., cov: 33)

Exomes 𝑓: 0.00080 ( 14 hom. )

Consequence

ZNF669
NM_001142572.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.766

Publications

2 publications found

Variant links:

Genes affected

ZNF669 (HGNC:25736): (zinc finger protein 669) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF669 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0040468276).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00671 (1022/152362) while in subpopulation AFR AF = 0.0228 (949/41588). AF 95% confidence interval is 0.0216. There are 15 homozygotes in GnomAd4. There are 474 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142572.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF669	NM_001142572.2	MANE Select	c.1123G>C	p.Val375Leu	missense	Exon 4 of 4	NP_001136044.1	Q96BR6-2
	ZNF669	NM_024804.3		c.1381G>C	p.Val461Leu	missense	Exon 4 of 4	NP_079080.2	Q96BR6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF669	ENST00000448299.7	TSL:1 MANE Select	c.1123G>C	p.Val375Leu	missense	Exon 4 of 4	ENSP00000404370.2	Q96BR6-2
	ZNF669	ENST00000343381.10	TSL:1	c.1381G>C	p.Val461Leu	missense	Exon 4 of 4	ENSP00000342818.6	Q96BR6-1

Frequencies

GnomAD3 genomes

AF:

0.00670

AC:

1020

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0228

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00716

GnomAD2 exomes

AF:

0.00199

AC:

483

AN:

242934

AF XY:

0.00147

show subpopulations

Gnomad AFR exome

AF:

0.0245

Gnomad AMR exome

AF:

0.00134

Gnomad ASJ exome

AF:

0.000106

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000257

Gnomad OTH exome

AF:

0.00168

GnomAD4 exome

AF:

0.000796

AC:

1151

AN:

1446562

Hom.:

Cov.:

AF XY:

0.000699

AC XY:

503

AN XY:

720100

show subpopulations

African (AFR)

AF:

0.0232

AC:

765

AN:

32982

American (AMR)

AF:

0.00156

AC:

AN:

43650

Ashkenazi Jewish (ASJ)

AF:

0.0000391

AC:

AN:

25554

East Asian (EAS)

AF:

0.00

AC:

AN:

39630

South Asian (SAS)

AF:

0.0000353

AC:

AN:

84898

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53042

Middle Eastern (MID)

AF:

0.00182

AC:

AN:

5506

European-Non Finnish (NFE)

AF:

0.000184

AC:

203

AN:

1101524

Other (OTH)

AF:

0.00169

AC:

101

AN:

59776

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

136

204

272

340

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.00671

AC:

1022

AN:

152362

Hom.:

Cov.:

AF XY:

0.00636

AC XY:

474

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.0228

AC:

949

AN:

41588

American (AMR)

AF:

0.00242

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68042

Other (OTH)

AF:

0.00709

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

100

150

200

250

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.000521

Hom.:

Bravo

AF:

0.00765

ESP6500AA

AF:

0.0241

AC:

106

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00224

AC:

272

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.51

(source)

DANN

Benign

0.14

DEOGEN2

Benign

0.0018

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0059

LIST_S2

Benign

0.42

MetaRNN

Benign

0.0040

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.34

PhyloP100

-0.77

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.12

REVEL

Benign

0.027

Sift

Benign

0.54

Sift4G

Pathogenic

0.0

Polyphen

0.0

Vest4

0.045

MutPred

0.44

Gain of sheet (P = 0.0101)

MVP

0.014

MPC

0.060

ClinPred

0.00027

GERP RS

-0.35

Varity_R

0.044

gMVP

0.033

Mutation Taster

=100/0

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over