20-45967623-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_022095.4(ZNF335):c.826G>A(p.Ala276Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00644 in 1,613,918 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0043 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0067 ( 50 hom. )

Consequence

ZNF335
NM_022095.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.0750

Publications

11 publications found

Variant links:

Genes affected

ZNF335 (HGNC:15807): (zinc finger protein 335) The protein encoded by this gene enhances transcriptional activation by ligand-bound nuclear hormone receptors. However, it does this not by direct interaction with the receptor, but by direct interaction with the nuclear hormone receptor transcriptional coactivator NRC. The encoded protein may function by altering local chromatin structure. [provided by RefSeq, Jul 2008]

ZNF335 Gene-Disease associations (from GenCC):

microcephalic primordial dwarfism due to ZNF335 deficiency
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ZNF335 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039509833).

BP6

Variant 20-45967623-C-T is Benign according to our data. Variant chr20-45967623-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00429 (653/152220) while in subpopulation NFE AF = 0.00719 (489/68010). AF 95% confidence interval is 0.00666. There are 0 homozygotes in GnomAd4. There are 295 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 50 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF335	NM_022095.4 link	c.826G>A	p.Ala276Thr	missense_variant	Exon 6 of 28	ENST00000322927.3	NP_071378.1	Q9H4Z2-1Q8IW09

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF335	ENST00000322927.3 link	c.826G>A	p.Ala276Thr	missense_variant	Exon 6 of 28	1	NM_022095.4	ENSP00000325326.2	Q9H4Z2-1
ZNF335	ENST00000476822.1 link	n.1159G>A		non_coding_transcript_exon_variant	Exon 4 of 5	2
ZNF335	ENST00000494955.1 link	n.1137G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.00429

AC:

653

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00142

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.00269

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00719

Gnomad OTH

AF:

0.00623

GnomAD2 exomes

AF:

0.00476

AC:

1196

AN:

251072

AF XY:

0.00495

show subpopulations

Gnomad AFR exome

AF:

0.00136

Gnomad AMR exome

AF:

0.00254

Gnomad ASJ exome

AF:

0.00845

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00116

Gnomad NFE exome

AF:

0.00795

Gnomad OTH exome

AF:

0.00507

GnomAD4 exome

AF:

0.00667

AC:

9748

AN:

1461698

Hom.:

Cov.:

AF XY:

0.00650

AC XY:

4729

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.00116

AC:

AN:

33480

American (AMR)

AF:

0.00266

AC:

119

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00773

AC:

202

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00140

AC:

121

AN:

86254

European-Finnish (FIN)

AF:

0.00139

AC:

AN:

53294

Middle Eastern (MID)

AF:

0.00919

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00793

AC:

8814

AN:

1111952

Other (OTH)

AF:

0.00540

AC:

326

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

628

1255

1883

2510

3138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

330

660

990

1320

1650

<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:

0.00429

AC:

653

AN:

152220

Hom.:

Cov.:

AF XY:

0.00396

AC XY:

295

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.00142

AC:

AN:

41534

American (AMR)

AF:

0.00268

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00778

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.000830

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00719

AC:

489

AN:

68010

Other (OTH)

AF:

0.00616

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

103

137

171

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:

0.00690

Hom.:

Bravo

AF:

0.00438

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00908

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00814

AC:

ExAC

AF:

0.00487

AC:

591

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00774

EpiControl

AF:

0.00936

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Apr 06, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ZNF335: BP4, BS2 -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 10, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Apr 07, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 22, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Microcephalic primordial dwarfism due to ZNF335 deficiency

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.71

CADD

Benign

7.3

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.060

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.075

LIST_S2

Benign

0.55

M_CAP

Benign

0.0070

MetaRNN

Benign

0.0040

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.81

PhyloP100

0.075

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.060

REVEL

Benign

0.011

Sift

Benign

0.37

Sift4G

Benign

0.40

Polyphen

0.0010

Vest4

0.15

MVP

0.055

MPC

0.15

ClinPred

0.00052

GERP RS

-2.6

Varity_R

0.021

gMVP

0.14

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over