rs183846665

Variant names:

Variant summary

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

The NM_007137.5(ZNF81):c.8C>T(p.Ala3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0161 in 1,207,460 control chromosomes in the GnomAD database, including 136 homozygotes. There are 6,115 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 13 hom., 344 hem., cov: 23)

Exomes 𝑓: 0.017 ( 123 hom. 5771 hem. )

Consequence

ZNF81
NM_007137.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.245

Publications

7 publications found

Variant links:

Genes affected

ZNF81 (HGNC:13156): (zinc finger protein 81) This gene encodes a protein that likely functions as a transcription factor. The protein contains an N-terminal KRAB domain and several C2H2-type zinc finger motifs. Mutations in this gene cause an X-linked form of intellectual disability (MRX45). Microduplication of a region of chromosome X including this gene has also been associated with other forms of intellectual disability. [provided by RefSeq, Jul 2017]

ZNF81 Gene-Disease associations (from GenCC):

non-syndromic X-linked intellectual disability
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
intellectual disability, X-linked 45
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
X-linked intellectual disability
Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

ZNF81 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=0.0035823584).

BP6

Variant X-47846275-C-T is Benign according to our data. Variant chrX-47846275-C-T is described in ClinVar as Benign. ClinVar VariationId is 130859.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 = 0.0117 (1309/112342) while in subpopulation NFE AF = 0.0187 (997/53230). AF 95% confidence interval is 0.0178. There are 13 homozygotes in GnomAd4. There are 344 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 Unknown,XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF81	NM_007137.5 link	c.8C>T	p.Ala3Val	missense_variant	Exon 2 of 5	ENST00000338637.13	NP_009068.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF81	ENST00000338637.13 link	c.8C>T	p.Ala3Val	missense_variant	Exon 2 of 5	3	NM_007137.5	ENSP00000341151.7

Frequencies

GnomAD3 genomes

AF:

0.0117

AC:

1313

AN:

112290

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00305

Gnomad AMI

AF:

0.0425

Gnomad AMR

AF:

0.0124

Gnomad ASJ

AF:

0.00604

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00110

Gnomad FIN

AF:

0.00323

Gnomad MID

AF:

0.0210

Gnomad NFE

AF:

0.0187

Gnomad OTH

AF:

0.0112

GnomAD2 exomes

AF:

0.00925

AC:

1607

AN:

173816

AF XY:

0.00854

show subpopulations

Gnomad AFR exome

AF:

0.00286

Gnomad AMR exome

AF:

0.00574

Gnomad ASJ exome

AF:

0.00589

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00294

Gnomad NFE exome

AF:

0.0163

Gnomad OTH exome

AF:

0.0103

GnomAD4 exome

AF:

0.0166

AC:

18178

AN:

1095118

Hom.:

123

Cov.:

AF XY:

0.0160

AC XY:

5771

AN XY:

361160

show subpopulations

African (AFR)

AF:

0.00239

AC:

AN:

26363

American (AMR)

AF:

0.00614

AC:

215

AN:

34996

Ashkenazi Jewish (ASJ)

AF:

0.00574

AC:

111

AN:

19324

East Asian (EAS)

AF:

0.0000332

AC:

AN:

30163

South Asian (SAS)

AF:

0.00158

AC:

AN:

53328

European-Finnish (FIN)

AF:

0.00343

AC:

138

AN:

40250

Middle Eastern (MID)

AF:

0.00318

AC:

AN:

3454

European-Non Finnish (NFE)

AF:

0.0201

AC:

16923

AN:

841296

Other (OTH)

AF:

0.0138

AC:

632

AN:

45944

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

688

1377

2065

2754

3442

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

636

1272

1908

2544

3180

<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:

0.0117

AC:

1309

AN:

112342

Hom.:

Cov.:

AF XY:

0.00997

AC XY:

344

AN XY:

34502

show subpopulations

African (AFR)

AF:

0.00304

AC:

AN:

30924

American (AMR)

AF:

0.0124

AC:

132

AN:

10630

Ashkenazi Jewish (ASJ)

AF:

0.00604

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3571

South Asian (SAS)

AF:

0.00110

AC:

AN:

2716

European-Finnish (FIN)

AF:

0.00323

AC:

AN:

6193

Middle Eastern (MID)

AF:

0.00461

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0187

AC:

997

AN:

53230

Other (OTH)

AF:

0.0111

AC:

AN:

1532

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

112

168

224

280

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:

0.0144

Hom.:

654

Bravo

AF:

0.0120

TwinsUK

AF:

0.0183

AC:

ALSPAC

AF:

0.0208

AC:

ESP6500AA

AF:

0.00260

AC:

ESP6500EA

AF:

0.0200

AC:

130

ExAC

AF:

0.00894

AC:

1081

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Dec 27, 2012

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

History of neurodevelopmental disorder

Benign:1

Nov 20, 2012

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.043

T;T;.;.

FATHMM_MKL

Benign

0.083

LIST_S2

Benign

0.52

.;T;T;T

MetaRNN

Benign

0.0036

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;L;.;.

PhyloP100

0.24

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.030

N;N;N;N

REVEL

Benign

0.027

Sift

Uncertain

0.0060

D;D;T;T

Sift4G

Uncertain

0.036

D;D;T;T

Polyphen

0.32

B;B;.;.

Vest4

0.073

MVP

0.44

MPC

0.15

ClinPred

0.0037

GERP RS

2.7

Varity_R

0.11

gMVP

0.15

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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