X-47846285-C-T

Variant names:

• chrX-47846285-C-T
• rs145478020
• NM_007137.5:c.18C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_007137.5(ZNF81):​c.18C>T​(p.Asp6Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0099 in 1,207,438 control chromosomes in the GnomAD database, including 529 homozygotes. There are 3,971 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (80 hom., 527 hem., cov: 23)
  • Exomes 𝑓: 0.0095 (449 hom. 3444 hem.)
• Consequence: ZNF81 NM_007137.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.680

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=-0.75).
• BP6: Variant X-47846285-C-T is Benign according to our data. Variant chrX-47846285-C-T is described in ClinVar as [Benign]. Clinvar id is 130853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-47846285-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.68 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF81	NM_007137.5	c.18C>T	p.Asp6Asp	synonymous_variant	Exon 2 of 5	ENST00000338637.13	NP_009068.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF81	ENST00000338637.13	c.18C>T	p.Asp6Asp	synonymous_variant	Exon 2 of 5	3	NM_007137.5	ENSP00000341151.7

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 1571 AN: 112152 Hom.: 80 Cov.: 23 AF XY: 0.0154 AC XY: 527 AN XY: 34308

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0699

Gnomad ASJ AF: 0.00265

Gnomad EAS AF: 0.163

Gnomad SAS AF: 0.0446

Gnomad FIN AF: 0.000163

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.000375

Gnomad OTH AF: 0.0259

GnomAD3 exomes AF: 0.0310 AC: 5397 AN: 173823 Hom.: 247 AF XY: 0.0261 AC XY: 1592 AN XY: 60901

Gnomad AFR exome AF: 0.00261

Gnomad AMR exome AF: 0.0939

Gnomad ASJ exome AF: 0.00315

Gnomad EAS exome AF: 0.162

Gnomad SAS exome AF: 0.0328

Gnomad FIN exome AF: 0.0000670

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.0236

GnomAD4 exome AF: 0.00948 AC: 10382 AN: 1095232 Hom.: 449 Cov.: 30 AF XY: 0.00953 AC XY: 3444 AN XY: 361240

Gnomad4 AFR exome AF: 0.00167

Gnomad4 AMR exome AF: 0.0929

Gnomad4 ASJ exome AF: 0.00238

Gnomad4 EAS exome AF: 0.140

Gnomad4 SAS exome AF: 0.0311

Gnomad4 FIN exome AF: 0.0000248

Gnomad4 NFE exome AF: 0.000307

Gnomad4 OTH exome AF: 0.0195

GnomAD4 genome AF: 0.0140 AC: 1567 AN: 112206 Hom.: 80 Cov.: 23 AF XY: 0.0153 AC XY: 527 AN XY: 34372

Gnomad4 AFR AF: 0.00204

Gnomad4 AMR AF: 0.0701

Gnomad4 ASJ AF: 0.00265

Gnomad4 EAS AF: 0.163

Gnomad4 SAS AF: 0.0436

Gnomad4 FIN AF: 0.000163

Gnomad4 NFE AF: 0.000376

Gnomad4 OTH AF: 0.0262

Alfa AF: 0.00463 Hom.: 37

Bravo AF: 0.0200

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Aug 07, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 24, 2014

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	2.7
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs145478020; hg19: chrX-47705684; COSMIC: COSV58482969; COSMIC: COSV58482969;