X-47914996-G-T

Variant names:

• chrX-47914996-G-T
• rs17147793
• NM_007137.5:c.350G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 14/20 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, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.673
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• intellectual disability, X-linked 45

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• X-linked intellectual disability

  Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 130855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 Unknown,XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007137.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF81	NM_007137.5	MANE Select	c.350G>T	p.Gly117Val	missense	Exon 5 of 5	NP_009068.2
	ZNF81	NM_001378152.1		c.350G>T	p.Gly117Val	missense	Exon 6 of 6	NP_001365081.1
	ZNF81	NM_001378153.1		c.350G>T	p.Gly117Val	missense	Exon 5 of 5	NP_001365082.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF81	ENST00000338637.13	TSL:3 MANE Select	c.350G>T	p.Gly117Val	missense	Exon 5 of 5	ENSP00000341151.7
	ZNF81	ENST00000376954.6	TSL:5	c.350G>T	p.Gly117Val	missense	Exon 6 of 6	ENSP00000366153.1
	ZNF81	ENST00000376950.4	TSL:5	c.277+19056G>T		intron	N/A	ENSP00000366149.4

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1215 AN: 111311 Hom.: 19 Cov.: 23

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

GnomAD2 exomes AF: 0.00306 AC: 536 AN: 174889 AF XY: 0.00197

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 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

African (AFR) AF: 0.0429 AC: 1127 AN: 26254

American (AMR) AF: 0.00130 AC: 45 AN: 34724

Ashkenazi Jewish (ASJ) AF: 0.0000520 AC: 1 AN: 19230

East Asian (EAS) AF: 0.00 AC: 0 AN: 30126

South Asian (SAS) AF: 0.000150 AC: 8 AN: 53318

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40384

Middle Eastern (MID) AF: 0.00196 AC: 8 AN: 4086

European-Non Finnish (NFE) AF: 0.0000369 AC: 31 AN: 839229

Other (OTH) AF: 0.00320 AC: 147 AN: 45899

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

African (AFR) AF: 0.0388 AC: 1189 AN: 30680

American (AMR) AF: 0.00202 AC: 21 AN: 10411

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2637

East Asian (EAS) AF: 0.00 AC: 0 AN: 3541

South Asian (SAS) AF: 0.00 AC: 0 AN: 2674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.000113 AC: 6 AN: 53051

Other (OTH) AF: 0.00528 AC: 8 AN: 1514

Alfa AF: 0.00500 Hom.: 109

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

May 06, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.67
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.015
Sift	Benign	0.39	T
Sift4G	Benign	0.12	T
Polyphen		0.23	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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17147793; hg19: chrX-47774395;