X-47915196-C-G

Position:

chrX-47915196-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_007137.5(ZNF81):c.550C>G(p.Leu184Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000259 in 1,202,595 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 79 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., 30 hem., cov: 23)

Exomes 𝑓: 0.00016 ( 0 hom. 49 hem. )

Consequence

ZNF81
NM_007137.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: -1.93

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0041686893).

BP6

Variant X-47915196-C-G is Benign according to our data. Variant chrX-47915196-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 590247.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-47915196-C-G is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 30 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF81	NM_007137.5 linkuse as main transcript	c.550C>G	p.Leu184Val	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.550C>G	p.Leu184Val	missense_variant	5/5	3	NM_007137.5	ENSP00000341151	P1
ZNF81	ENST00000376954.6 linkuse as main transcript	c.550C>G	p.Leu184Val	missense_variant	6/6	5		ENSP00000366153	P1
ZNF81	ENST00000376950.4 linkuse as main transcript	c.277+19256C>G		intron_variant		5		ENSP00000366149

Frequencies

GnomAD3 genomes

AF:

0.00122

AC:

136

AN:

111796

Hom.:

Cov.:

AF XY:

0.000853

AC XY:

AN XY:

33998

show subpopulations

Gnomad AFR

AF:

0.00419

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000381

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:

0.00

Gnomad OTH

AF:

0.00200

GnomAD3 exomes

AF:

0.000351

AC:

AN:

173901

Hom.:

AF XY:

0.000195

AC XY:

AN XY:

61609

show subpopulations

Gnomad AFR exome

AF:

0.00417

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000127

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000160

AC:

174

AN:

1090747

Hom.:

Cov.:

AF XY:

0.000137

AC XY:

AN XY:

358317

show subpopulations

Gnomad4 AFR exome

AF:

0.00508

Gnomad4 AMR exome

AF:

0.000412

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000715

Gnomad4 OTH exome

AF:

0.000416

GnomAD4 genome

AF:

0.00122

AC:

137

AN:

111848

Hom.:

Cov.:

AF XY:

0.000881

AC XY:

AN XY:

34060

show subpopulations

Gnomad4 AFR

AF:

0.00421

Gnomad4 AMR

AF:

0.000381

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00197

Alfa

AF:

0.000215

Hom.:

Bravo

AF:

0.00145

ESP6500AA

AF:

0.00524

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000356

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

ZNF81-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 27, 2022

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). -

History of neurodevelopmental disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2013

This alteration is classified as likely benign based on a combination of the following: 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.88

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.33

DANN

Benign

0.78

DEOGEN2

Benign

0.027

T;T

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.016

.;T

M_CAP

Benign

0.038

MetaRNN

Benign

0.0042

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.22

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

0.38

N;N

REVEL

Benign

0.018

Sift

Benign

0.97

T;T

Sift4G

Benign

0.35

T;T

Polyphen

0.0080

B;B

Vest4

0.052

MVP

0.26

MPC

0.16

ClinPred

0.0065

GERP RS

-0.83

Varity_R

0.048

gMVP

0.022

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