X-47895893-A-G

Variant names:

• chrX-47895893-A-G
• rs781949174
• NM_007137.5:c.230A>G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_007137.5(ZNF81):​c.230A>G​(p.Glu77Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000456 in 1,097,305 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 2 hem.)
• Consequence: ZNF81 NM_007137.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.71

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35561717).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF81	NM_007137.5	c.230A>G	p.Glu77Gly	missense_variant	Exon 4 of 5	ENST00000338637.13	NP_009068.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF81	ENST00000338637.13	c.230A>G	p.Glu77Gly	missense_variant	Exon 4 of 5	3	NM_007137.5	ENSP00000341151.7
ZNF81	ENST00000376954.6	c.230A>G	p.Glu77Gly	missense_variant	Exon 5 of 6	5		ENSP00000366153.1
ZNF81	ENST00000376950.4	c.230A>G	p.Glu77Gly	missense_variant	Exon 4 of 5	5		ENSP00000366149.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000549 AC: 1 AN: 182145 Hom.: 0 AF XY: 0.0000149 AC XY: 1 AN XY: 66935

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1097305 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 2 AN XY: 362821

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000594

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.230A>G (p.E77G) alteration is located in exon 4 (coding exon 3) of the ZNF81 gene. This alteration results from a A to G substitution at nucleotide position 230, causing the glutamic acid (E) at amino acid position 77 to be replaced by a glycine (G). 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	0.16
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.18	T;T;.
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.29	.;T;T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.6	M;M;.
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-4.6	D;D;D
REVEL	Benign	0.14
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.032	D;D;D
Polyphen		0.46	P;P;.
Vest4		0.29
MutPred		0.45		Loss of solvent accessibility (P = 0.0098);Loss of solvent accessibility (P = 0.0098);Loss of solvent accessibility (P = 0.0098);
MVP		0.62
MPC		0.37
ClinPred		0.91	D
GERP RS		4.1
Varity_R		0.29
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs781949174; hg19: chrX-47755292;