chrX-47916141-A-G

Position:

chrX-47916141-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_007137.5(ZNF81):c.1495A>G(p.Ile499Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,210,032 control chromosomes in the GnomAD database, including 22 homozygotes. There are 1,676 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0041 ( 5 hom., 137 hem., cov: 23)

Exomes 𝑓: 0.0043 ( 17 hom. 1539 hem. )

Consequence

ZNF81
NM_007137.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.48

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0049043).

BP6

Variant X-47916141-A-G is Benign according to our data. Variant chrX-47916141-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 212695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-47916141-A-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF81	NM_007137.5 linkuse as main transcript	c.1495A>G	p.Ile499Val	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.1495A>G	p.Ile499Val	missense_variant	5/5	3	NM_007137.5	ENSP00000341151	P1
ZNF81	ENST00000376954.6 linkuse as main transcript	c.1495A>G	p.Ile499Val	missense_variant	6/6	5		ENSP00000366153	P1
ZNF81	ENST00000376950.4 linkuse as main transcript	c.277+20201A>G		intron_variant		5		ENSP00000366149

Frequencies

GnomAD3 genomes

AF:

0.00406

AC:

454

AN:

111889

Hom.:

Cov.:

AF XY:

0.00402

AC XY:

137

AN XY:

34053

show subpopulations

Gnomad AFR

AF:

0.000649

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00503

Gnomad ASJ

AF:

0.0272

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000373

Gnomad FIN

AF:

0.00344

Gnomad MID

AF:

0.0336

Gnomad NFE

AF:

0.00504

Gnomad OTH

AF:

0.00735

GnomAD3 exomes

AF:

0.00451

AC:

821

AN:

181886

Hom.:

AF XY:

0.00502

AC XY:

338

AN XY:

67370

show subpopulations

Gnomad AFR exome

AF:

0.000479

Gnomad AMR exome

AF:

0.00190

Gnomad ASJ exome

AF:

0.0296

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00252

Gnomad FIN exome

AF:

0.00444

Gnomad NFE exome

AF:

0.00497

Gnomad OTH exome

AF:

0.00425

GnomAD4 exome

AF:

0.00433

AC:

4750

AN:

1098088

Hom.:

Cov.:

AF XY:

0.00423

AC XY:

1539

AN XY:

363512

show subpopulations

Gnomad4 AFR exome

AF:

0.000492

Gnomad4 AMR exome

AF:

0.00188

Gnomad4 ASJ exome

AF:

0.0287

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00218

Gnomad4 FIN exome

AF:

0.00390

Gnomad4 NFE exome

AF:

0.00421

Gnomad4 OTH exome

AF:

0.00534

GnomAD4 genome

AF:

0.00406

AC:

454

AN:

111944

Hom.:

Cov.:

AF XY:

0.00402

AC XY:

137

AN XY:

34118

show subpopulations

Gnomad4 AFR

AF:

0.000648

Gnomad4 AMR

AF:

0.00503

Gnomad4 ASJ

AF:

0.0272

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000375

Gnomad4 FIN

AF:

0.00344

Gnomad4 NFE

AF:

0.00504

Gnomad4 OTH

AF:

0.00725

Alfa

AF:

0.00533

Hom.:

Bravo

AF:

0.00413

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00450

AC:

ESP6500AA

AF:

0.00157

AC:

ESP6500EA

AF:

0.00566

AC:

ExAC

AF:

0.00410

AC:

498

EpiCase

AF:

0.00606

EpiControl

AF:

0.00611

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 10, 2017	- -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.87

BayesDel_noAF

Benign

-1.0

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.015

T;T

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.086

.;T

M_CAP

Benign

0.0012

MetaRNN

Benign

0.0049

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.5

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

0.20

N;N

REVEL

Benign

0.030

Sift

Benign

0.99

T;T

Sift4G

Benign

0.29

T;T

Polyphen

0.0

B;B

Vest4

0.030

MVP

0.52

MPC

0.13

ClinPred

0.0059

GERP RS

1.6

Varity_R

0.040

gMVP

0.048

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