X-47915116-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.507

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]

ACMG classification

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: {Uncertain_significance=1, Benign=2, Likely_benign=1}. Variant chrX-47915116-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF81	NM_007137.5	c.470A>G	p.Asn157Ser	missense_variant	5/5	ENST00000338637.13

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00518 AC: 578 AN: 111558 Hom.: 2 Cov.: 22 AF XY: 0.00468 AC XY: 158 AN XY: 33732

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.: 2 AF XY: 0.00515 AC XY: 311 AN XY: 60347

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.: 26 Cov.: 30 AF XY: 0.00762 AC XY: 2733 AN XY: 358811

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.: 2 Cov.: 22 AF XY: 0.00465 AC XY: 157 AN XY: 33792

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: 23

ALSPAC AF: 0.00865 AC: 25

ESP6500AA AF: 0.00130 AC: 4

ESP6500EA AF: 0.00705 AC: 45

ExAC AF: 0.00467 AC: 564

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	T
BayesDel_noAF	Benign	-1.1
Cadd	Benign	5.2
Dann	Benign	0.58
DEOGEN2	Benign	0.040	T;T
FATHMM_MKL	Benign	0.018	N
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.0057	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.74	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
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	T
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

Other links and lift over

dbSNP: rs41312157; hg19: chrX-47774515; COSMIC: COSV58576278;