X-47915103-A-T

Variant names:

• chrX-47915103-A-T
• rs1373985841
• NM_007137.5:c.457A>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.457A>T​(p.Thr153Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 23)
• Consequence: ZNF81 NM_007137.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.31
• 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=0.060171783).

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.457A>T	p.Thr153Ser	missense	Exon 5 of 5	NP_009068.2	P51508
	ZNF81	NM_001378152.1		c.457A>T	p.Thr153Ser	missense	Exon 6 of 6	NP_001365081.1	P51508
	ZNF81	NM_001378153.1		c.457A>T	p.Thr153Ser	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.457A>T	p.Thr153Ser	missense	Exon 5 of 5	ENSP00000341151.7	P51508
	ZNF81	ENST00000376954.6	TSL:5	c.457A>T	p.Thr153Ser	missense	Exon 6 of 6	ENSP00000366153.1	P51508
	ZNF81	ENST00000853619.1		c.457A>T	p.Thr153Ser	missense	Exon 5 of 5	ENSP00000523678.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

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	0.099
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.035
DANN	Benign	0.084
DEOGEN2	Benign	0.034	T
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.054	T
M_CAP	Benign	0.00086	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.60	N
PhyloP100		-1.3
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.011
Sift	Benign	0.43	T
Sift4G	Benign	0.93	T
Polyphen		0.0	B
Vest4		0.054
MutPred		0.31		Gain of disorder (P = 0.0655)
MVP		0.19
MPC		0.14
ClinPred		0.058	T
GERP RS		-1.5
Varity_R		0.042
gMVP		0.046
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: rs1373985841; hg19: chrX-47774502;