X-47915103-A-T

Variant summary

Our verdict is Likely benign. Variant got -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. 14/20 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

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060171783).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF81	NM_007137.5	c.457A>T	p.Thr153Ser	missense_variant	5/5	ENST00000338637.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF81	ENST00000338637.13	c.457A>T	p.Thr153Ser	missense_variant	5/5	3	NM_007137.5	P1
ZNF81	ENST00000376954.6	c.457A>T	p.Thr153Ser	missense_variant	6/6	5		P1
ZNF81	ENST00000376950.4	c.277+19163A>T		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2022

The c.457A>T (p.T153S) alteration is located in exon 5 (coding exon 4) of the ZNF81 gene. This alteration results from a A to T substitution at nucleotide position 457, causing the threonine (T) at amino acid position 153 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;T
FATHMM_MKL	Benign	0.033	N
M_CAP	Benign	0.00086	T
MetaRNN	Benign	0.060	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.60	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.73	N;N
REVEL	Benign	0.011
Sift	Benign	0.43	T;T
Sift4G	Benign	0.93	T;T
Polyphen		0.0	B;B
Vest4		0.054
MutPred		0.31		Gain of disorder (P = 0.0655);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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-47774502;