Genetic Variant ZNF350:p.Ile69Thr (chr19-51968610-A-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_021632.4(ZNF350):c.206T>C(p.Ile69Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,614,038 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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. I69V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0027 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 7 hom. )

Consequence

ZNF350
NM_021632.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.77

Publications

10 publications found

Variant links:

Genes affected

ZNF350 (HGNC:16656): (zinc finger protein 350) Enables DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II intronic transcription regulatory region sequence-specific DNA binding activity. Involved in negative regulation of transcription by RNA polymerase II. Located in nuclear body. Part of transcription repressor complex. [provided by Alliance of Genome Resources, Apr 2022]

ZNF350 links:

ZNF350-AS1 (HGNC:48598): (ZNF350 antisense RNA 1)

ZNF350-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005890608).

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF350	NM_021632.4 link	c.206T>C	p.Ile69Thr	missense_variant	Exon 4 of 5	ENST00000243644.9	NP_067645.3	Q9GZX5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF350	ENST00000243644.9 link	c.206T>C	p.Ile69Thr	missense_variant	Exon 4 of 5	1	NM_021632.4	ENSP00000243644.3		Q9GZX5

Frequencies

GnomAD3 genomes

AF:

0.00266

AC:

404

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00572

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00175

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00157

AC:

396

AN:

251446

AF XY:

0.00154

show subpopulations

Gnomad AFR exome

AF:

0.00671

Gnomad AMR exome

AF:

0.00150

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00184

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00185

AC:

2707

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00179

AC XY:

1305

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00744

AC:

249

AN:

33478

American (AMR)

AF:

0.00165

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00111

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00202

AC:

2249

AN:

1112000

Other (OTH)

AF:

0.00159

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

136

271

407

542

678

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

288

384

480

<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:

0.00267

AC:

406

AN:

152172

Hom.:

Cov.:

AF XY:

0.00255

AC XY:

190

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.00576

AC:

239

AN:

41526

American (AMR)

AF:

0.00275

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5142

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00175

AC:

119

AN:

68012

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00219

Hom.:

Bravo

AF:

0.00323

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.00704

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.00161

AC:

196

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.00256

EpiControl

AF:

0.00273

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.0010

(source)

DANN

Benign

0.12

DEOGEN2

Benign

0.036

T;.

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.0046

T;T

M_CAP

Benign

0.00087

MetaRNN

Benign

0.0059

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.18

N;.

PhyloP100

-2.8

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.2

N;.

REVEL

Benign

0.016

Sift

Benign

1.0

T;.

Sift4G

Benign

0.89

T;T

Polyphen

0.0

B;.

Vest4

0.032

MVP

0.055

MPC

0.25

ClinPred

0.0016

GERP RS

-2.9

Varity_R

0.024

gMVP

0.011

Mutation Taster

=98/2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over