rs1556890406

Variant names:

• chrX-47915090-A-T
• rs1556890406
• NM_007137.5:c.444A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_007137.5(ZNF81):​c.444A>T​(p.Lys148Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,207,077 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: ZNF81 NM_007137.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.388
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06657097).

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.444A>T	p.Lys148Asn	missense	Exon 5 of 5	NP_009068.2	P51508
	ZNF81	NM_001378152.1		c.444A>T	p.Lys148Asn	missense	Exon 6 of 6	NP_001365081.1	P51508
	ZNF81	NM_001378153.1		c.444A>T	p.Lys148Asn	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.444A>T	p.Lys148Asn	missense	Exon 5 of 5	ENSP00000341151.7	P51508
	ZNF81	ENST00000376954.6	TSL:5	c.444A>T	p.Lys148Asn	missense	Exon 6 of 6	ENSP00000366153.1	P51508
	ZNF81	ENST00000853619.1		c.444A>T	p.Lys148Asn	missense	Exon 5 of 5	ENSP00000523678.1

Frequencies

GnomAD3 genomes AF: 0.00000901 AC: 1 AN: 111010 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1096067 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 361747

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

African (AFR) AF: 0.0000759 AC: 2 AN: 26335

American (AMR) AF: 0.00 AC: 0 AN: 34861

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19304

East Asian (EAS) AF: 0.00 AC: 0 AN: 30149

South Asian (SAS) AF: 0.00 AC: 0 AN: 53469

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40471

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4119

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841351

Other (OTH) AF: 0.00 AC: 0 AN: 46008

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000901 AC: 1 AN: 111010 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33230

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

African (AFR) AF: 0.0000327 AC: 1 AN: 30535

American (AMR) AF: 0.00 AC: 0 AN: 10424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2634

East Asian (EAS) AF: 0.00 AC: 0 AN: 3535

South Asian (SAS) AF: 0.00 AC: 0 AN: 2632

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52984

Other (OTH) AF: 0.00 AC: 0 AN: 1490

⚠️ 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: 0.00 Hom.: 0

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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	4.4
DANN	Benign	0.78
DEOGEN2	Benign	0.054	T
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.20	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.88	L
PhyloP100		0.39
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.040
Sift	Benign	0.28	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.063
MutPred		0.41		Loss of methylation at K148 (P = 0.0204)
MVP		0.27
MPC		0.18
ClinPred		0.12	T
GERP RS		1.7
Varity_R		0.16
gMVP		0.17
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: rs1556890406; hg19: chrX-47774489;