rs186251256

chrX-47915200-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.336

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 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 GnomAd at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF81	NM_007137.5	c.554C>T	p.Ser185Leu	missense_variant	5/5	ENST00000338637.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF81	ENST00000338637.13	c.554C>T	p.Ser185Leu	missense_variant	5/5	3	NM_007137.5	P1
ZNF81	ENST00000376954.6	c.554C>T	p.Ser185Leu	missense_variant	6/6	5		P1
ZNF81	ENST00000376950.4	c.277+19260C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00961 AC: 1074 AN: 111729 Hom.: 6 Cov.: 22 AF XY: 0.00799 AC XY: 271 AN XY: 33923

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.: 6 AF XY: 0.00849 AC XY: 524 AN XY: 61707

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.: 73 Cov.: 31 AF XY: 0.0128 AC XY: 4587 AN XY: 358101

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.: 6 Cov.: 22 AF XY: 0.00800 AC XY: 272 AN XY: 33985

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: 48

ALSPAC AF: 0.0180 AC: 52

ESP6500AA AF: 0.00262 AC: 8

ESP6500EA AF: 0.0164 AC: 104

ExAC AF: 0.00881 AC: 1064

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.84
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T
FATHMM_MKL	Benign	0.29	N
MetaRNN	Benign	0.0053	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	0.87	N;N
PrimateAI	Benign	0.34	T
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	T
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

Other links and lift over

dbSNP: rs186251256; hg19: chrX-47774599; COSMIC: COSV99061334;