rs186251256

Positions:

chrX-47915200-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_007137.5(ZNF81):c.554C>T(p.Ser185Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,202,294 control chromosomes in the GnomAD database, including 79 homozygotes. There are 4,859 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0096 ( 6 hom., 272 hem., cov: 22)

Exomes 𝑓: 0.013 ( 73 hom. 4587 hem. )

Consequence

ZNF81
NM_007137.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.336

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005334437).

BP6

Variant X-47915200-C-T is Benign according to our data. Variant chrX-47915200-C-T is described in ClinVar as [Benign]. Clinvar id is 130857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-47915200-C-T is described in Lovd as [Benign]. Variant chrX-47915200-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0133 (14557/1090513) while in subpopulation NFE AF= 0.0157 (13207/838581). AF 95% confidence interval is 0.0155. There are 73 homozygotes in gnomad4_exome. There are 4587 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF81	NM_007137.5 linkuse as main transcript	c.554C>T	p.Ser185Leu	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.554C>T	p.Ser185Leu	missense_variant	5/5	3	NM_007137.5	ENSP00000341151	P1
ZNF81	ENST00000376954.6 linkuse as main transcript	c.554C>T	p.Ser185Leu	missense_variant	6/6	5		ENSP00000366153	P1
ZNF81	ENST00000376950.4 linkuse as main transcript	c.277+19260C>T		intron_variant		5		ENSP00000366149

Frequencies

GnomAD3 genomes

AF:

0.00961

AC:

1074

AN:

111729

Hom.:

Cov.:

AF XY:

0.00799

AC XY:

271

AN XY:

33923

show subpopulations

Gnomad AFR

AF:

0.00250

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00982

Gnomad ASJ

AF:

0.00909

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00149

Gnomad FIN

AF:

0.00399

Gnomad MID

AF:

0.00417

Gnomad NFE

AF:

0.0153

Gnomad OTH

AF:

0.0181

GnomAD3 exomes

AF:

0.00853

AC:

1484

AN:

174025

Hom.:

AF XY:

0.00849

AC XY:

524

AN XY:

61707

show subpopulations

Gnomad AFR exome

AF:

0.00221

Gnomad AMR exome

AF:

0.00491

Gnomad ASJ exome

AF:

0.00950

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00165

Gnomad FIN exome

AF:

0.00693

Gnomad NFE exome

AF:

0.0138

Gnomad OTH exome

AF:

0.00973

GnomAD4 exome

AF:

0.0133

AC:

14557

AN:

1090513

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

4587

AN XY:

358101

show subpopulations

Gnomad4 AFR exome

AF:

0.00189

Gnomad4 AMR exome

AF:

0.00556

Gnomad4 ASJ exome

AF:

0.0106

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00178

Gnomad4 FIN exome

AF:

0.00748

Gnomad4 NFE exome

AF:

0.0157

Gnomad4 OTH exome

AF:

0.0109

GnomAD4 genome

AF:

0.00960

AC:

1073

AN:

111781

Hom.:

Cov.:

AF XY:

0.00800

AC XY:

272

AN XY:

33985

show subpopulations

Gnomad4 AFR

AF:

0.00250

Gnomad4 AMR

AF:

0.00981

Gnomad4 ASJ

AF:

0.00909

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00149

Gnomad4 FIN

AF:

0.00399

Gnomad4 NFE

AF:

0.0153

Gnomad4 OTH

AF:

0.0178

Alfa

AF:

0.0129

Hom.:

516

Bravo

AF:

0.00994

TwinsUK

AF:

0.0129

AC:

ALSPAC

AF:

0.0180

AC:

ESP6500AA

AF:

0.00262

AC:

ESP6500EA

AF:

0.0164

AC:

104

ExAC

AF:

0.00881

AC:

1064

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 05, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 08, 2015	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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.84

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;T

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.25

.;T

MetaRNN

Benign

0.0053

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;L

MutationTaster

Benign

0.87

N;N

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-3.5

D;D

REVEL

Benign

0.030

Sift

Benign

0.072

T;T

Sift4G

Benign

0.094

T;T

Polyphen

0.029

B;B

Vest4

0.072

MVP

0.40

MPC

0.14

ClinPred

0.011

GERP RS

3.2

Varity_R

0.22

gMVP

0.15

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

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