rs145478020

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 6 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 -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 VariationId is 130853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF81	NM_007137.5	MANE Select	c.18C>T	p.Asp6Asp	synonymous	Exon 2 of 5	NP_009068.2	P51508
	ZNF81	NM_001378152.1		c.18C>T	p.Asp6Asp	synonymous	Exon 3 of 6	NP_001365081.1	P51508
	ZNF81	NM_001378153.1		c.18C>T	p.Asp6Asp	synonymous	Exon 2 of 5	NP_001365082.1	P51508

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF81	ENST00000338637.13	TSL:3 MANE Select	c.18C>T	p.Asp6Asp	synonymous	Exon 2 of 5	ENSP00000341151.7	P51508
	ZNF81	ENST00000334937.8	TSL:1	c.18C>T	p.Asp6Asp	synonymous	Exon 3 of 4	ENSP00000334641.4	B1AJV1
	ZNF81	ENST00000376954.6	TSL:5	c.18C>T	p.Asp6Asp	synonymous	Exon 3 of 6	ENSP00000366153.1	P51508

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 1571 AN: 112152 Hom.: 80 Cov.: 23

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

GnomAD2 exomes AF: 0.0310 AC: 5397 AN: 173823 AF XY: 0.0261

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 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

African (AFR) AF: 0.00167 AC: 44 AN: 26371

American (AMR) AF: 0.0929 AC: 3241 AN: 34882

Ashkenazi Jewish (ASJ) AF: 0.00238 AC: 46 AN: 19335

East Asian (EAS) AF: 0.140 AC: 4230 AN: 30135

South Asian (SAS) AF: 0.0311 AC: 1660 AN: 53381

European-Finnish (FIN) AF: 0.0000248 AC: 1 AN: 40255

Middle Eastern (MID) AF: 0.00141 AC: 5 AN: 3536

European-Non Finnish (NFE) AF: 0.000307 AC: 258 AN: 841366

Other (OTH) AF: 0.0195 AC: 897 AN: 45971

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

African (AFR) AF: 0.00204 AC: 63 AN: 30883

American (AMR) AF: 0.0701 AC: 743 AN: 10602

Ashkenazi Jewish (ASJ) AF: 0.00265 AC: 7 AN: 2646

East Asian (EAS) AF: 0.163 AC: 575 AN: 3532

South Asian (SAS) AF: 0.0436 AC: 118 AN: 2707

European-Finnish (FIN) AF: 0.000163 AC: 1 AN: 6153

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

European-Non Finnish (NFE) AF: 0.000376 AC: 20 AN: 53256

Other (OTH) AF: 0.0262 AC: 40 AN: 1526

Alfa AF: 0.00463 Hom.: 37

Bravo AF: 0.0200

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	2.7
DANN	Benign	0.86
PhyloP100		-0.68
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs145478020; hg19: chrX-47705684; COSMIC: COSV58482969; COSMIC: COSV58482969;