X-47846275-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.8C>T(p.Ala3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0161 in 1,207,460 control chromosomes in the GnomAD database, including 136 homozygotes. There are 6,115 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (13 hom., 344 hem., cov: 23)
  • Exomes 𝑓: 0.017 (123 hom. 5771 hem.)
• Consequence: ZNF81 NM_007137.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.245

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=0.0035823584).
• BP6: Variant X-47846275-C-T is Benign according to our data. Variant chrX-47846275-C-T is described in ClinVar as [Benign]. Clinvar id is 130859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-47846275-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0117 (1309/112342) while in subpopulation NFE AF= 0.0187 (997/53230). AF 95% confidence interval is 0.0178. There are 13 homozygotes in gnomad4. There are 344 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF81	NM_007137.5	c.8C>T	p.Ala3Val	missense_variant	2/5	ENST00000338637.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF81	ENST00000338637.13	c.8C>T	p.Ala3Val	missense_variant	2/5	3	NM_007137.5	P1

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1313 AN: 112290 Hom.: 14 Cov.: 23 AF XY: 0.00999 AC XY: 344 AN XY: 34440

Gnomad AFR AF: 0.00305

Gnomad AMI AF: 0.0425

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.00604

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00110

Gnomad FIN AF: 0.00323

Gnomad MID AF: 0.0210

Gnomad NFE AF: 0.0187

Gnomad OTH AF: 0.0112

GnomAD3 exomes AF: 0.00925 AC: 1607 AN: 173816 Hom.: 5 AF XY: 0.00854 AC XY: 519 AN XY: 60784

Gnomad AFR exome AF: 0.00286

Gnomad AMR exome AF: 0.00574

Gnomad ASJ exome AF: 0.00589

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00130

Gnomad FIN exome AF: 0.00294

Gnomad NFE exome AF: 0.0163

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.0166 AC: 18178 AN: 1095118 Hom.: 123 Cov.: 30 AF XY: 0.0160 AC XY: 5771 AN XY: 361160

Gnomad4 AFR exome AF: 0.00239

Gnomad4 AMR exome AF: 0.00614

Gnomad4 ASJ exome AF: 0.00574

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.00158

Gnomad4 FIN exome AF: 0.00343

Gnomad4 NFE exome AF: 0.0201

Gnomad4 OTH exome AF: 0.0138

GnomAD4 genome AF: 0.0117 AC: 1309 AN: 112342 Hom.: 13 Cov.: 23 AF XY: 0.00997 AC XY: 344 AN XY: 34502

Gnomad4 AFR AF: 0.00304

Gnomad4 AMR AF: 0.0124

Gnomad4 ASJ AF: 0.00604

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00110

Gnomad4 FIN AF: 0.00323

Gnomad4 NFE AF: 0.0187

Gnomad4 OTH AF: 0.0111

Alfa AF: 0.0153 Hom.: 644

Bravo AF: 0.0120

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0208 AC: 60

ESP6500AA AF: 0.00260 AC: 9

ESP6500EA AF: 0.0200 AC: 130

ExAC AF: 0.00894 AC: 1081

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 27, 2012

- -

History of neurodevelopmental disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2012

This alteration is classified as 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	0.16
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	16
Dann	Uncertain	1.0
DEOGEN2	Benign	0.043	T;T;.;.
FATHMM_MKL	Benign	0.083	N
MetaRNN	Benign	0.0036	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.030	N;N;N;N
REVEL	Benign	0.027
Sift	Uncertain	0.0060	D;D;T;T
Sift4G	Uncertain	0.036	D;D;T;T
Polyphen		0.32	B;B;.;.
Vest4		0.073
MVP		0.44
MPC		0.15
ClinPred		0.0037	T
GERP RS		2.7
Varity_R		0.11
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs183846665; hg19: chrX-47705674; COSMIC: COSV99061323; COSMIC: COSV99061323;