X-47914996-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_007137.5(ZNF81):c.350G>T(p.Gly117Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00215 in 1,204,611 control chromosomes in the GnomAD database, including 36 homozygotes. There are 677 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G117D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (19 hom., 318 hem., cov: 23)
  • Exomes 𝑓: 0.0013 (17 hom. 359 hem.)
• Consequence: ZNF81 NM_007137.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.673

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.041061997).
• BP6: Variant X-47914996-G-T is Benign according to our data. Variant chrX-47914996-G-T is described in ClinVar as [Benign]. Clinvar id is 130855.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.011 (1224/111361) while in subpopulation AFR AF= 0.0388 (1189/30680). AF 95% confidence interval is 0.0369. There are 19 homozygotes in gnomad4. There are 318 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF81	NM_007137.5	c.350G>T	p.Gly117Val	missense_variant	5/5	ENST00000338637.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF81	ENST00000338637.13	c.350G>T	p.Gly117Val	missense_variant	5/5	3	NM_007137.5	P1
ZNF81	ENST00000376954.6	c.350G>T	p.Gly117Val	missense_variant	6/6	5		P1
ZNF81	ENST00000376950.4	c.277+19056G>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1215 AN: 111311 Hom.: 19 Cov.: 23 AF XY: 0.00928 AC XY: 311 AN XY: 33501

Gnomad AFR AF: 0.0385

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00202

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: 0.000113

Gnomad OTH AF: 0.00535

GnomAD3 exomes AF: 0.00306 AC: 536 AN: 174889 Hom.: 8 AF XY: 0.00197 AC XY: 121 AN XY: 61521

Gnomad AFR exome AF: 0.0403

Gnomad AMR exome AF: 0.00132

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000115

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000891

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.00125 AC: 1367 AN: 1093250 Hom.: 17 Cov.: 30 AF XY: 0.00100 AC XY: 359 AN XY: 359108

Gnomad4 AFR exome AF: 0.0429

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.0000520

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000150

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.00320

GnomAD4 genome AF: 0.0110 AC: 1224 AN: 111361 Hom.: 19 Cov.: 23 AF XY: 0.00948 AC XY: 318 AN XY: 33561

Gnomad4 AFR AF: 0.0388

Gnomad4 AMR AF: 0.00202

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000113

Gnomad4 OTH AF: 0.00528

Alfa AF: 0.00303 Hom.: 15

Bravo AF: 0.0131

ESP6500AA AF: 0.0403 AC: 124

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00310 AC: 374

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 06, 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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.94
Cadd	Benign	6.5
Dann	Benign	0.36
DEOGEN2	Benign	0.049	T;T
FATHMM_MKL	Benign	0.12	N
MetaRNN	Benign	0.041	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	0.056	P;P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.015
Sift	Benign	0.39	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.23	B;B
Vest4		0.061
MVP		0.28
MPC		0.38
ClinPred		0.0095	T
GERP RS		1.3
Varity_R		0.096
gMVP		0.11

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: rs17147793; hg19: chrX-47774395;