chrX-47915116-A-G

Position:

chrX-47915116-A-G

Variant summary

Our verdict is Likely benign. Variant got -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. 13/22 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -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 id is 130856.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=2}. Variant chrX-47915116-A-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF81	NM_007137.5 linkuse as main transcript	c.470A>G	p.Asn157Ser	missense_variant	5/5	ENST00000338637.13	NP_009068.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ZNF81	ENST00000338637.13 linkuse as main transcript	c.470A>G	p.Asn157Ser	missense_variant	5/5	3	NM_007137.5	ENSP00000341151	P1
ZNF81	ENST00000376954.6 linkuse as main transcript	c.470A>G	p.Asn157Ser	missense_variant	6/6	5		ENSP00000366153	P1
ZNF81	ENST00000376950.4 linkuse as main transcript	c.277+19176A>G		intron_variant		5		ENSP00000366149

Frequencies

GnomAD3 genomes

AF:

0.00518

AC:

578

AN:

111558

Hom.:

Cov.:

AF XY:

0.00468

AC XY:

158

AN XY:

33732

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

GnomAD3 exomes

AF:

0.00492

AC:

852

AN:

173163

Hom.:

AF XY:

0.00515

AC XY:

311

AN XY:

60347

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 SAS exome

AF:

0.00107

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

Gnomad4 AFR exome

AF:

0.00103

Gnomad4 AMR exome

AF:

0.00277

Gnomad4 ASJ exome

AF:

0.00554

Gnomad4 EAS exome

AF:

0.0000332

Gnomad4 SAS exome

AF:

0.00105

Gnomad4 FIN exome

AF:

0.00255

Gnomad4 NFE exome

AF:

0.00886

Gnomad4 OTH exome

AF:

0.00791

GnomAD4 genome

AF:

0.00516

AC:

576

AN:

111608

Hom.:

Cov.:

AF XY:

0.00465

AC XY:

157

AN XY:

33792

show subpopulations

Gnomad4 AFR

AF:

0.000942

Gnomad4 AMR

AF:

0.00181

Gnomad4 ASJ

AF:

0.00417

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00184

Gnomad4 NFE

AF:

0.00940

Gnomad4 OTH

AF:

0.00461

Alfa

AF:

0.00876

Hom.:

336

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

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 31, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2016	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 22, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 19, 2017	- -

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

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

MutationTaster

Benign

1.0

N;N

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over