X-47888018-A-T

Position:

• chrX-47888018-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_007137.5(ZNF81):​c.74A>T​(p.Asp25Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ZNF81 NM_007137.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.05

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF81	NM_007137.5	c.74A>T	p.Asp25Val	missense_variant	3/5	ENST00000338637.13	NP_009068.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF81	ENST00000338637.13	c.74A>T	p.Asp25Val	missense_variant	3/5	3	NM_007137.5	ENSP00000341151	P1
ZNF81	ENST00000334937.8	c.74A>T	p.Asp25Val	missense_variant	4/4	1		ENSP00000334641
ZNF81	ENST00000376954.6	c.74A>T	p.Asp25Val	missense_variant	4/6	5		ENSP00000366153	P1
ZNF81	ENST00000376950.4	c.74A>T	p.Asp25Val	missense_variant	3/5	5		ENSP00000366149

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

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

Nov 30, 2022

The c.74A>T (p.D25V) alteration is located in exon 3 (coding exon 2) of the ZNF81 gene. This alteration results from a A to T substitution at nucleotide position 74, causing the aspartic acid (D) at amino acid position 25 to be replaced by a valine (V). 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	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T;.;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	.;D;T;T
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Pathogenic	4.9	H;H;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-7.2	D;D;D;D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.82
MutPred		0.81		Loss of disorder (P = 0.0242);Loss of disorder (P = 0.0242);Loss of disorder (P = 0.0242);Loss of disorder (P = 0.0242);
MVP		0.73
MPC		0.80
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.88
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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-47747417;