Genetic Variant ZNF81:p.Ser31Asn (chrX-47888036-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_007137.5(ZNF81):c.92G>A(p.Ser31Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,208,924 control chromosomes in the GnomAD database, including 1 homozygotes. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 1 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.0000091 ( 0 hom. 3 hem. )

Consequence

ZNF81
NM_007137.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.11

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2637285).

BS2

High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF81	NM_007137.5 link	c.92G>A	p.Ser31Asn	missense_variant	Exon 3 of 5	ENST00000338637.13	NP_009068.2	P51508

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF81	ENST00000338637.13 link	c.92G>A	p.Ser31Asn	missense_variant	Exon 3 of 5	3	NM_007137.5	ENSP00000341151.7	P51508
ZNF81	ENST00000334937.8 link	c.92G>A	p.Ser31Asn	missense_variant	Exon 4 of 4	1		ENSP00000334641.4	B1AJV1
ZNF81	ENST00000376954.6 link	c.92G>A	p.Ser31Asn	missense_variant	Exon 4 of 6	5		ENSP00000366153.1	P51508
ZNF81	ENST00000376950.4 link	c.92G>A	p.Ser31Asn	missense_variant	Exon 3 of 5	5		ENSP00000366149.4	B1AJV2

Frequencies

GnomAD3 genomes

AF:

0.0000721

AC:

AN:

110891

Hom.:

Cov.:

AF XY:

0.0000302

AC XY:

AN XY:

33069

show subpopulations

Gnomad AFR

AF:

0.000263

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD3 exomes

AF:

0.0000218

AC:

AN:

183157

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67725

show subpopulations

Gnomad AFR exome

AF:

0.000229

Gnomad AMR exome

AF:

0.0000365

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000911

AC:

AN:

1098033

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

363409

show subpopulations

Gnomad4 AFR exome

AF:

0.000189

Gnomad4 AMR exome

AF:

0.0000284

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:

0.00000238

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000721

AC:

AN:

110891

Hom.:

Cov.:

AF XY:

0.0000302

AC XY:

AN XY:

33069

show subpopulations

Gnomad4 AFR

AF:

0.000263

Gnomad4 AMR

AF:

0.00

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:

0.00

Alfa

AF:

0.0000119

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.92G>A (p.S31N) alteration is located in exon 3 (coding exon 2) of the ZNF81 gene. This alteration results from a G to A substitution at nucleotide position 92, causing the serine (S) at amino acid position 31 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.079

T;T;.;.

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.28

.;T;T;T

M_CAP

Benign

0.0042

MetaRNN

Benign

0.26

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.8

M;M;.;.

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.7

N;N;N;N

REVEL

Benign

0.19

Sift

Uncertain

0.0030

D;D;D;D

Sift4G

Uncertain

0.0070

D;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.62

MVP

0.21

MPC

0.64

ClinPred

0.80

GERP RS

3.1

Varity_R

0.27

gMVP

0.46

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