rs189835360

Variant names:

• chrX-47915063-A-G
• rs189835360
• NM_007137.5:c.417A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_007137.5(ZNF81):​c.417A>G​(p.Ile139Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000263 in 1,207,614 control chromosomes in the GnomAD database, including 1 homozygotes. There are 77 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., 40 hem., cov: 22)
  • Exomes 𝑓: 0.00015 (1 hom. 37 hem.)
• Consequence: ZNF81 NM_007137.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.310
• Publications: 1 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043881834).
• BP6: Variant X-47915063-A-G is Benign according to our data. Variant chrX-47915063-A-G is described in ClinVar as Benign. ClinVar VariationId is 212697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 40 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.417A>G	p.Ile139Met	missense	Exon 5 of 5	NP_009068.2	P51508
	ZNF81	NM_001378152.1		c.417A>G	p.Ile139Met	missense	Exon 6 of 6	NP_001365081.1	P51508
	ZNF81	NM_001378153.1		c.417A>G	p.Ile139Met	missense	Exon 5 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.417A>G	p.Ile139Met	missense	Exon 5 of 5	ENSP00000341151.7	P51508
	ZNF81	ENST00000376954.6	TSL:5	c.417A>G	p.Ile139Met	missense	Exon 6 of 6	ENSP00000366153.1	P51508
	ZNF81	ENST00000853619.1		c.417A>G	p.Ile139Met	missense	Exon 5 of 5	ENSP00000523678.1

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 155 AN: 111229 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00474

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000575

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: 0.0000377

Gnomad OTH AF: 0.00134

GnomAD2 exomes AF: 0.000331 AC: 59 AN: 177991 AF XY: 0.000171

Gnomad AFR exome AF: 0.00375

Gnomad AMR exome AF: 0.000411

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000458

GnomAD4 exome AF: 0.000145 AC: 159 AN: 1096334 Hom.: 1 Cov.: 30 AF XY: 0.000102 AC XY: 37 AN XY: 362002

African (AFR) AF: 0.00399 AC: 105 AN: 26341

American (AMR) AF: 0.000573 AC: 20 AN: 34891

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19311

East Asian (EAS) AF: 0.00 AC: 0 AN: 30150

South Asian (SAS) AF: 0.0000561 AC: 3 AN: 53515

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4122

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841481

Other (OTH) AF: 0.000630 AC: 29 AN: 46033

GnomAD4 genome AF: 0.00142 AC: 158 AN: 111280 Hom.: 0 Cov.: 22 AF XY: 0.00119 AC XY: 40 AN XY: 33482

African (AFR) AF: 0.00483 AC: 148 AN: 30663

American (AMR) AF: 0.000574 AC: 6 AN: 10448

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2637

East Asian (EAS) AF: 0.00 AC: 0 AN: 3548

South Asian (SAS) AF: 0.00 AC: 0 AN: 2664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5880

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.0000377 AC: 2 AN: 53027

Other (OTH) AF: 0.00132 AC: 2 AN: 1514

Alfa AF: 0.000645 Hom.: 36

Bravo AF: 0.00182

ESP6500AA AF: 0.00384 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000373 AC: 45

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	ZNF81-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	9.4
DANN	Uncertain	0.98
DEOGEN2	Benign	0.043	T
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.81	L
PhyloP100		-0.31
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.079
Sift	Benign	0.12	T
Sift4G	Benign	0.24	T
Polyphen		0.16	B
Vest4		0.12
MVP		0.35
MPC		0.16
ClinPred		0.011	T
GERP RS		-3.0
Varity_R		0.086
gMVP		0.22
Mutation Taster		=100/0	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: rs189835360; hg19: chrX-47774462;