X-47888073-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_007137.5(ZNF81):c.129A>G(p.Arg43=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,208,415 control chromosomes in the GnomAD database, including 11 homozygotes. There are 367 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (6 hom., 164 hem., cov: 22)
  • Exomes 𝑓: 0.00068 (5 hom. 203 hem.)
• Consequence: ZNF81 NM_007137.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.785

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant X-47888073-A-G is Benign according to our data. Variant chrX-47888073-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 590232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.785 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00625 (691/110551) while in subpopulation AFR AF= 0.0218 (662/30363). AF 95% confidence interval is 0.0204. There are 6 homozygotes in gnomad4. There are 164 alleles in male gnomad4 subpopulation. Median coverage is 22. 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.129A>G	p.Arg43=	synonymous_variant	3/5	ENST00000338637.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF81	ENST00000338637.13	c.129A>G	p.Arg43=	synonymous_variant	3/5	3	NM_007137.5	P1
ZNF81	ENST00000334937.8	c.129A>G	p.Arg43=	synonymous_variant	4/4	1
ZNF81	ENST00000376954.6	c.129A>G	p.Arg43=	synonymous_variant	4/6	5		P1
ZNF81	ENST00000376950.4	c.129A>G	p.Arg43=	synonymous_variant	3/5	5

Frequencies

GnomAD3 genomes AF: 0.00624 AC: 690 AN: 110502 Hom.: 6 Cov.: 22 AF XY: 0.00501 AC XY: 164 AN XY: 32720

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

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: 0.00

Gnomad OTH AF: 0.00405

GnomAD3 exomes AF: 0.00189 AC: 345 AN: 182310 Hom.: 3 AF XY: 0.00107 AC XY: 72 AN XY: 67048

Gnomad AFR exome AF: 0.0232

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000369

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000676 AC: 742 AN: 1097864 Hom.: 5 Cov.: 31 AF XY: 0.000559 AC XY: 203 AN XY: 363258

Gnomad4 AFR exome AF: 0.0227

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000190

Gnomad4 OTH exome AF: 0.00135

GnomAD4 genome AF: 0.00625 AC: 691 AN: 110551 Hom.: 6 Cov.: 22 AF XY: 0.00500 AC XY: 164 AN XY: 32779

Gnomad4 AFR AF: 0.0218

Gnomad4 AMR AF: 0.00221

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00400

Alfa AF: 0.00330 Hom.: 14

Bravo AF: 0.00739

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ZNF81-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

History of neurodevelopmental disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2013

This alteration is classified as likely 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
BayesDel_noAF	Benign	-0.91
Cadd	Benign	6.5
Dann	Benign	0.49

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: rs148626389; hg19: chrX-47747472;