rs11091216

Variant names:

• chrX-47888133-C-T
• rs11091216
• ENST00000334937.8:c.189C>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.181+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0254 in 1,204,317 control chromosomes in the GnomAD database, including 357 homozygotes. There are 9,876 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (34 hom., 708 hem., cov: 22)
  • Exomes 𝑓: 0.026 (323 hom. 9168 hem.)
• Consequence: ZNF81 NM_007137.5 splice_region, intron
• Scores: Splicing: ADA: 0.0004466
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0740
• Publications: 2 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 (BayesDel_noAF=-0.87).
• BP6: Variant X-47888133-C-T is Benign according to our data. Variant chrX-47888133-C-T is described in ClinVar as Benign. ClinVar VariationId is 95449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0197 (2184/110984) while in subpopulation NFE AF = 0.0284 (1505/52971). AF 95% confidence interval is 0.0272. There are 34 homozygotes in GnomAd4. There are 708 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 XL,Unknown 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF81	NM_007137.5	MANE Select	c.181+8C>T		splice_region intron	N/A	NP_009068.2	P51508
	ZNF81	NM_001378152.1		c.181+8C>T		splice_region intron	N/A	NP_001365081.1	P51508
	ZNF81	NM_001378153.1		c.181+8C>T		splice_region intron	N/A	NP_001365082.1	P51508

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF81	ENST00000334937.8	TSL:1	c.189C>T	p.Asp63Asp	synonymous	Exon 4 of 4	ENSP00000334641.4	B1AJV1
	ZNF81	ENST00000338637.13	TSL:3 MANE Select	c.181+8C>T		splice_region intron	N/A	ENSP00000341151.7	P51508
	ZNF81	ENST00000376954.6	TSL:5	c.181+8C>T		splice_region intron	N/A	ENSP00000366153.1	P51508

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 2183 AN: 110933 Hom.: 34 Cov.: 22

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.00438

Gnomad AMR AF: 0.00507

Gnomad ASJ AF: 0.0148

Gnomad EAS AF: 0.000564

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.0732

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.0284

Gnomad OTH AF: 0.0128

GnomAD2 exomes AF: 0.0215 AC: 3664 AN: 170744 AF XY: 0.0212

Gnomad AFR exome AF: 0.00299

Gnomad AMR exome AF: 0.00480

Gnomad ASJ exome AF: 0.00835

Gnomad EAS exome AF: 0.0000761

Gnomad FIN exome AF: 0.0791

Gnomad NFE exome AF: 0.0256

Gnomad OTH exome AF: 0.0211

GnomAD4 exome AF: 0.0260 AC: 28381 AN: 1093333 Hom.: 323 Cov.: 31 AF XY: 0.0255 AC XY: 9168 AN XY: 359297

African (AFR) AF: 0.00300 AC: 79 AN: 26325

American (AMR) AF: 0.00492 AC: 170 AN: 34518

Ashkenazi Jewish (ASJ) AF: 0.0103 AC: 198 AN: 19308

East Asian (EAS) AF: 0.000133 AC: 4 AN: 30092

South Asian (SAS) AF: 0.0157 AC: 842 AN: 53517

European-Finnish (FIN) AF: 0.0739 AC: 2973 AN: 40234

Middle Eastern (MID) AF: 0.0135 AC: 55 AN: 4067

European-Non Finnish (NFE) AF: 0.0275 AC: 23116 AN: 839370

Other (OTH) AF: 0.0206 AC: 944 AN: 45902

GnomAD4 genome AF: 0.0197 AC: 2184 AN: 110984 Hom.: 34 Cov.: 22 AF XY: 0.0213 AC XY: 708 AN XY: 33190

African (AFR) AF: 0.00318 AC: 97 AN: 30492

American (AMR) AF: 0.00506 AC: 53 AN: 10475

Ashkenazi Jewish (ASJ) AF: 0.0148 AC: 39 AN: 2644

East Asian (EAS) AF: 0.000566 AC: 2 AN: 3536

South Asian (SAS) AF: 0.0141 AC: 37 AN: 2619

European-Finnish (FIN) AF: 0.0732 AC: 428 AN: 5846

Middle Eastern (MID) AF: 0.00461 AC: 1 AN: 217

European-Non Finnish (NFE) AF: 0.0284 AC: 1505 AN: 52971

Other (OTH) AF: 0.0127 AC: 19 AN: 1499

Alfa AF: 0.0263 Hom.: 219

Bravo AF: 0.0141

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	-0.87
CADD	Benign	2.2
DANN	Benign	0.51
PhyloP100		-0.074
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00045
dbscSNV1_RF	Benign	0.034
SpliceAI score (max)		0.030		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: rs11091216; hg19: chrX-47747532;