chrX-47846258-C-T

Variant names:

• chrX-47846258-C-T
• rs782609524
• NM_007137.5:c.-10C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_007137.5(ZNF81):​c.-10C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,206,213 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000020 (0 hom. 13 hem.)
• Consequence: ZNF81 NM_007137.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.470
• Publications: 0 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BS2: High Hemizygotes in GnomAdExome4 at 13 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF81	NM_007137.5	MANE Select	c.-10C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 5	NP_009068.2	P51508
	ZNF81	NM_007137.5	MANE Select	c.-10C>T		5_prime_UTR	Exon 2 of 5	NP_009068.2	P51508
	ZNF81	NM_001378152.1		c.-10C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 6	NP_001365081.1	P51508

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF81	ENST00000338637.13	TSL:3 MANE Select	c.-10C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 5	ENSP00000341151.7	P51508
	ZNF81	ENST00000334937.8	TSL:1	c.-10C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 4	ENSP00000334641.4	B1AJV1
	ZNF81	ENST00000338637.13	TSL:3 MANE Select	c.-10C>T		5_prime_UTR	Exon 2 of 5	ENSP00000341151.7	P51508

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112165 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000369

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000525 AC: 9 AN: 171293 AF XY: 0.000102

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000131

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000201 AC: 22 AN: 1094048 Hom.: 0 Cov.: 30 AF XY: 0.0000361 AC XY: 13 AN XY: 360376

African (AFR) AF: 0.00 AC: 0 AN: 26350

American (AMR) AF: 0.00 AC: 0 AN: 34865

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19299

East Asian (EAS) AF: 0.00 AC: 0 AN: 30138

South Asian (SAS) AF: 0.000339 AC: 18 AN: 53103

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40212

Middle Eastern (MID) AF: 0.000598 AC: 2 AN: 3342

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840812

Other (OTH) AF: 0.0000218 AC: 1 AN: 45927

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112165 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34325

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30843

American (AMR) AF: 0.00 AC: 0 AN: 10585

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3583

South Asian (SAS) AF: 0.000369 AC: 1 AN: 2707

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53226

Other (OTH) AF: 0.00 AC: 0 AN: 1501

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.5
DANN	Benign	0.96
PhyloP100		0.47
Mutation Taster		=300/0	polymorphism

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: rs782609524; hg19: chrX-47705657;