rs41312157

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_007137.5(ZNF81):c.470A>G(p.Asn157Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00732 in 1,204,219 control chromosomes in the GnomAD database, including 28 homozygotes. There are 2,890 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0052 ( 2 hom., 157 hem., cov: 22)

Exomes 𝑓: 0.0075 ( 26 hom. 2733 hem. )

Consequence

ZNF81
NM_007137.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -0.507

Publications

5 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: Likely_benign. The variant received -5 ACMG points.

BP6

Variant X-47915116-A-G is Benign according to our data. Variant chrX-47915116-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130856.

BS2

High Homozygotes in GnomAd4 at 2 Unknown,XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF81	NM_007137.5 link	c.470A>G	p.Asn157Ser	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.470A>G	p.Asn157Ser	missense_variant	Exon 5 of 5	3	NM_007137.5	ENSP00000341151.7
ZNF81	ENST00000376954.6 link	c.470A>G	p.Asn157Ser	missense_variant	Exon 6 of 6	5		ENSP00000366153.1
ZNF81	ENST00000376950.4 link	c.277+19176A>G		intron_variant	Intron 4 of 4	5		ENSP00000366149.4

Frequencies

GnomAD3 genomes

AF:

0.00518

AC:

578

AN:

111558

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000944

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00181

Gnomad ASJ

AF:

0.00417

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00184

Gnomad MID

AF:

0.00418

Gnomad NFE

AF:

0.00941

Gnomad OTH

AF:

0.00467

GnomAD2 exomes

AF:

0.00492

AC:

852

AN:

173163

AF XY:

0.00515

show subpopulations

Gnomad AFR exome

AF:

0.00107

Gnomad AMR exome

AF:

0.00247

Gnomad ASJ exome

AF:

0.00656

Gnomad EAS exome

AF:

0.0000765

Gnomad FIN exome

AF:

0.00173

Gnomad NFE exome

AF:

0.00834

Gnomad OTH exome

AF:

0.00709

GnomAD4 exome

AF:

0.00754

AC:

8234

AN:

1092611

Hom.:

Cov.:

AF XY:

0.00762

AC XY:

2733

AN XY:

358811

show subpopulations

African (AFR)

AF:

0.00103

AC:

AN:

26154

American (AMR)

AF:

0.00277

AC:

AN:

34260

Ashkenazi Jewish (ASJ)

AF:

0.00554

AC:

106

AN:

19124

East Asian (EAS)

AF:

0.0000332

AC:

AN:

30124

South Asian (SAS)

AF:

0.00105

AC:

AN:

52502

European-Finnish (FIN)

AF:

0.00255

AC:

103

AN:

40360

Middle Eastern (MID)

AF:

0.0107

AC:

AN:

4094

European-Non Finnish (NFE)

AF:

0.00886

AC:

7440

AN:

840130

Other (OTH)

AF:

0.00791

AC:

363

AN:

45863

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

359

718

1078

1437

1796

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

270

540

810

1080

1350

<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:

0.00516

AC:

576

AN:

111608

Hom.:

Cov.:

AF XY:

0.00465

AC XY:

157

AN XY:

33792

show subpopulations

African (AFR)

AF:

0.000942

AC:

AN:

30775

American (AMR)

AF:

0.00181

AC:

AN:

10489

Ashkenazi Jewish (ASJ)

AF:

0.00417

AC:

AN:

2639

East Asian (EAS)

AF:

0.00

AC:

AN:

3538

South Asian (SAS)

AF:

0.00

AC:

AN:

2652

European-Finnish (FIN)

AF:

0.00184

AC:

AN:

5984

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00940

AC:

499

AN:

53111

Other (OTH)

AF:

0.00461

AC:

AN:

1517

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

105

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:

0.00778

Hom.:

383

Bravo

AF:

0.00508

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00865

AC:

ESP6500AA

AF:

0.00130

AC:

ESP6500EA

AF:

0.00705

AC:

ExAC

AF:

0.00467

AC:

564

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Aug 31, 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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

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

- -

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

- -

not specified

Benign:2

Jan 22, 2016

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: seen in unaffected individuals, 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. -

May 19, 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

0.077

BayesDel_addAF

Benign

-0.94

BayesDel_noAF

Benign

-1.1

CADD

Benign

5.2

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.040

T;T

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.49

.;T

M_CAP

Benign

0.0013

MetaRNN

Benign

0.0057

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.74

N;N

PhyloP100

-0.51

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.017

Sift

Benign

0.42

T;T

Sift4G

Benign

0.69

T;T

Polyphen

0.0030

B;B

Vest4

0.0080

MVP

0.20

MPC

0.12

ClinPred

0.0031

GERP RS

-1.3

Varity_R

0.048

gMVP

0.091

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.41

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.41

Position offset: -1

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