rs189835360

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.417A>G(p.Ile139Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000263 in 1,207,614 control chromosomes in the GnomAD database, including 1 homozygotes. There are 77 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 0.0014 ( 0 hom., 40 hem., cov: 22)

Exomes 𝑓: 0.00015 ( 1 hom. 37 hem. )

Consequence

ZNF81
NM_007137.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.310

Publications

1 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=0.0043881834).

BP6

Variant X-47915063-A-G is Benign according to our data. Variant chrX-47915063-A-G is described in ClinVar as Benign. ClinVar VariationId is 212697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 40 Unknown,XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF81	NM_007137.5 link	c.417A>G	p.Ile139Met	missense_variant	Exon 5 of 5	ENST00000338637.13	NP_009068.2	P51508

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF81	ENST00000338637.13 link	c.417A>G	p.Ile139Met	missense_variant	Exon 5 of 5	3	NM_007137.5	ENSP00000341151.7	P51508
ZNF81	ENST00000376954.6 link	c.417A>G	p.Ile139Met	missense_variant	Exon 6 of 6	5		ENSP00000366153.1	P51508
ZNF81	ENST00000376950.4 link	c.277+19123A>G		intron_variant	Intron 4 of 4	5		ENSP00000366149.4	B1AJV2

Frequencies

GnomAD3 genomes

AF:

0.00139

AC:

155

AN:

111229

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00474

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000575

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000377

Gnomad OTH

AF:

0.00134

GnomAD2 exomes

AF:

0.000331

AC:

AN:

177991

AF XY:

0.000171

show subpopulations

Gnomad AFR exome

AF:

0.00375

Gnomad AMR exome

AF:

0.000411

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000458

GnomAD4 exome

AF:

0.000145

AC:

159

AN:

1096334

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

362002

show subpopulations

African (AFR)

AF:

0.00399

AC:

105

AN:

26341

American (AMR)

AF:

0.000573

AC:

AN:

34891

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19311

East Asian (EAS)

AF:

0.00

AC:

AN:

30150

South Asian (SAS)

AF:

0.0000561

AC:

AN:

53515

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40490

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4122

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

841481

Other (OTH)

AF:

0.000630

AC:

AN:

46033

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00142

AC:

158

AN:

111280

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

AN XY:

33482

show subpopulations

African (AFR)

AF:

0.00483

AC:

148

AN:

30663

American (AMR)

AF:

0.000574

AC:

AN:

10448

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2637

East Asian (EAS)

AF:

0.00

AC:

AN:

3548

South Asian (SAS)

AF:

0.00

AC:

AN:

2664

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5880

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.0000377

AC:

AN:

53027

Other (OTH)

AF:

0.00132

AC:

AN:

1514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.000645

Hom.:

Bravo

AF:

0.00182

ESP6500AA

AF:

0.00384

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000373

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Sep 18, 2017

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ZNF81-related disorder

Benign:1

Feb 28, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.86

CADD

Benign

9.4

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.043

T;T

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.27

.;T

MetaRNN

Benign

0.0044

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.81

L;L

PhyloP100

-0.31

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.18

N;N

REVEL

Benign

0.079

Sift

Benign

0.12

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.16

B;B

Vest4

0.12

MVP

0.35

MPC

0.16

ClinPred

0.011

GERP RS

-3.0

Varity_R

0.086

gMVP

0.22

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