rs182239885

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_007137.5(ZNF81):c.1495A>G(p.Ile499Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,210,032 control chromosomes in the GnomAD database, including 22 homozygotes. There are 1,676 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 5 hom., 137 hem., cov: 23)

Exomes 𝑓: 0.0043 ( 17 hom. 1539 hem. )

Consequence

ZNF81
NM_007137.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.48

Publications

6 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0049043).

BP6

Variant X-47916141-A-G is Benign according to our data. Variant chrX-47916141-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 5 Unknown,XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF81	NM_007137.5 link	c.1495A>G	p.Ile499Val	missense_variant	Exon 5 of 5	ENST00000338637.13	NP_009068.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ZNF81	ENST00000338637.13 link	c.1495A>G	p.Ile499Val	missense_variant	Exon 5 of 5	3	NM_007137.5	ENSP00000341151.7
ZNF81	ENST00000376954.6 link	c.1495A>G	p.Ile499Val	missense_variant	Exon 6 of 6	5		ENSP00000366153.1
ZNF81	ENST00000376950.4 link	c.277+20201A>G		intron_variant	Intron 4 of 4	5		ENSP00000366149.4

Frequencies

GnomAD3 genomes

AF:

0.00406

AC:

454

AN:

111889

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000649

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00503

Gnomad ASJ

AF:

0.0272

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000373

Gnomad FIN

AF:

0.00344

Gnomad MID

AF:

0.0336

Gnomad NFE

AF:

0.00504

Gnomad OTH

AF:

0.00735

GnomAD2 exomes

AF:

0.00451

AC:

821

AN:

181886

AF XY:

0.00502

show subpopulations

Gnomad AFR exome

AF:

0.000479

Gnomad AMR exome

AF:

0.00190

Gnomad ASJ exome

AF:

0.0296

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00444

Gnomad NFE exome

AF:

0.00497

Gnomad OTH exome

AF:

0.00425

GnomAD4 exome

AF:

0.00433

AC:

4750

AN:

1098088

Hom.:

Cov.:

AF XY:

0.00423

AC XY:

1539

AN XY:

363512

show subpopulations

African (AFR)

AF:

0.000492

AC:

AN:

26398

American (AMR)

AF:

0.00188

AC:

AN:

35141

Ashkenazi Jewish (ASJ)

AF:

0.0287

AC:

556

AN:

19382

East Asian (EAS)

AF:

0.00

AC:

AN:

30202

South Asian (SAS)

AF:

0.00218

AC:

118

AN:

54147

European-Finnish (FIN)

AF:

0.00390

AC:

158

AN:

40519

Middle Eastern (MID)

AF:

0.0109

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00421

AC:

3548

AN:

842073

Other (OTH)

AF:

0.00534

AC:

246

AN:

46090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

211

422

632

843

1054

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

130

260

390

520

650

<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:

0.00406

AC:

454

AN:

111944

Hom.:

Cov.:

AF XY:

0.00402

AC XY:

137

AN XY:

34118

show subpopulations

African (AFR)

AF:

0.000648

AC:

AN:

30863

American (AMR)

AF:

0.00503

AC:

AN:

10540

Ashkenazi Jewish (ASJ)

AF:

0.0272

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3557

South Asian (SAS)

AF:

0.000375

AC:

AN:

2668

European-Finnish (FIN)

AF:

0.00344

AC:

AN:

6098

Middle Eastern (MID)

AF:

0.0367

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00504

AC:

268

AN:

53148

Other (OTH)

AF:

0.00725

AC:

AN:

1517

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00457

Hom.:

Bravo

AF:

0.00413

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00450

AC:

ESP6500AA

AF:

0.00157

AC:

ESP6500EA

AF:

0.00566

AC:

ExAC

AF:

0.00410

AC:

498

EpiCase

AF:

0.00606

EpiControl

AF:

0.00611

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 10, 2017

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

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Dec 12, 2017

Genetic Services Laboratory, University of Chicago

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

0.074

BayesDel_addAF

Benign

-0.87

BayesDel_noAF

Benign

-1.0

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.015

T;T

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.086

.;T

M_CAP

Benign

0.0012

MetaRNN

Benign

0.0049

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.5

N;N

PhyloP100

-1.5

PrimateAI

Benign

0.41

PROVEAN

Benign

0.20

N;N

REVEL

Benign

0.030

Sift

Benign

0.99

T;T

Sift4G

Benign

0.29

T;T

Polyphen

0.0

B;B

Vest4

0.030

MVP

0.52

MPC

0.13

ClinPred

0.0059

GERP RS

1.6

Varity_R

0.040

gMVP

0.048

Mutation Taster

=100/0

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over