dbSNP rs28933691: ZNF81:p.Ser179Asn (chrX-47915182-G-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BS2

The NM_007137.5(ZNF81):c.536G>A(p.Ser179Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,201,666 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 59 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., 4 hem., cov: 22)

Exomes 𝑓: 0.00016 ( 0 hom. 55 hem. )

Consequence

ZNF81
NM_007137.5 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: -0.483

Publications

3 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 -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.83

BS2

High Hemizygotes in GnomAd4 at 4 Unknown,XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF81	NM_007137.5 link	c.536G>A	p.Ser179Asn	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.536G>A	p.Ser179Asn	missense_variant	Exon 5 of 5	3	NM_007137.5	ENSP00000341151.7
ZNF81	ENST00000376954.6 link	c.536G>A	p.Ser179Asn	missense_variant	Exon 6 of 6	5		ENSP00000366153.1
ZNF81	ENST00000376950.4 link	c.277+19242G>A		intron_variant	Intron 4 of 4	5		ENSP00000366149.4

Frequencies

GnomAD3 genomes

AF:

0.000143

AC:

AN:

111726

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000286

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:

0.000245

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000984

AC:

AN:

172779

AF XY:

0.0000824

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000194

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000153

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000161

AC:

175

AN:

1089940

Hom.:

Cov.:

AF XY:

0.000154

AC XY:

AN XY:

357740

show subpopulations

African (AFR)

AF:

0.0000386

AC:

AN:

25919

American (AMR)

AF:

0.000118

AC:

AN:

33838

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19019

East Asian (EAS)

AF:

0.00

AC:

AN:

30090

South Asian (SAS)

AF:

0.00

AC:

AN:

52542

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40291

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4068

European-Non Finnish (NFE)

AF:

0.000198

AC:

166

AN:

838473

Other (OTH)

AF:

0.0000875

AC:

AN:

45700

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

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:

0.000143

AC:

AN:

111726

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

33924

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30784

American (AMR)

AF:

0.000286

AC:

AN:

10480

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2635

East Asian (EAS)

AF:

0.00

AC:

AN:

3565

South Asian (SAS)

AF:

0.00

AC:

AN:

2706

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6013

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.000245

AC:

AN:

53125

Other (OTH)

AF:

0.00

AC:

AN:

1500

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.000180

Hom.:

Bravo

AF:

0.000144

ExAC

AF:

0.000116

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Intellectual disability, X-linked 45

Uncertain:1

May 01, 2004

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.033

(source)

DANN

Benign

0.22

DEOGEN2

Benign

0.036

T;T

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.25

.;T

M_CAP

Benign

0.017

MetaRNN

Pathogenic

0.83

D;D

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.29

N;N

PhyloP100

-0.48

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.12

N;N

REVEL

Benign

0.099

Sift

Benign

0.94

T;T

Sift4G

Benign

0.73

T;T

Polyphen

0.0

B;B

Vest4

0.63

MVP

0.28

MPC

0.14

ClinPred

0.014

GERP RS

2.2

Varity_R

0.053

gMVP

0.095

Mutation Taster

=96/4

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