X-47976348-C-T

Variant names:

• chrX-47976348-C-T
• rs782476080
• NM_001007088.2:c.1682G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001007088.2(ZNF182):​c.1682G>A​(p.Arg561Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000165 in 1,093,984 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 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)
  • Exomes 𝑓: 0.000016 (0 hom. 4 hem.)
• Consequence: ZNF182 NM_001007088.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.589
• Publications: 1 publications found

Genes affected

ZNF182 (HGNC:13001): (zinc finger protein 182) Zinc-finger proteins bind nucleic acids and play important roles in various cellular functions, including cell proliferation, differentiation, and apoptosis. This gene encodes a zinc finger protein, and belongs to the krueppel C2H2-type zinc-finger protein family. It may be involved in transcriptional regulation. Multiple alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, May 2010]

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12729082).
• BS2: High Hemizygotes in GnomAdExome4 at 4 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001007088.2. 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
	ZNF182	NM_001007088.2	MANE Select	c.1682G>A	p.Arg561Gln	missense	Exon 6 of 6	NP_001007089.1	P17025-2
	ZNF182	NM_001178099.2		c.1739G>A	p.Arg580Gln	missense	Exon 7 of 7	NP_001171570.1	P17025-1
	ZNF182	NM_006962.2		c.1739G>A	p.Arg580Gln	missense	Exon 7 of 7	NP_008893.1	P17025-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF182	ENST00000376943.8	TSL:1 MANE Select	c.1682G>A	p.Arg561Gln	missense	Exon 6 of 6	ENSP00000366142.4	P17025-2
	ZNF182	ENST00000396965.5	TSL:2	c.1739G>A	p.Arg580Gln	missense	Exon 7 of 7	ENSP00000380165.1	P17025-1
	ZNF182	ENST00000897864.1		c.1682G>A	p.Arg561Gln	missense	Exon 5 of 5	ENSP00000567923.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000399 AC: 7 AN: 175617 AF XY: 0.0000329

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000229

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000165 AC: 18 AN: 1093984 Hom.: 0 Cov.: 31 AF XY: 0.0000111 AC XY: 4 AN XY: 359864

African (AFR) AF: 0.00 AC: 0 AN: 26256

American (AMR) AF: 0.000174 AC: 6 AN: 34512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19103

East Asian (EAS) AF: 0.00 AC: 0 AN: 30159

South Asian (SAS) AF: 0.0000377 AC: 2 AN: 53087

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40419

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4111

European-Non Finnish (NFE) AF: 0.0000119 AC: 10 AN: 840416

Other (OTH) AF: 0.00 AC: 0 AN: 45921

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000412 AC: 5

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	Uncertain	0.56
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T
FATHMM_MKL	Benign	0.00075	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.59
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.078
Sift	Benign	0.082	T
Sift4G	Benign	0.28	T
Polyphen		0.98	D
Vest4		0.25
MutPred		0.43		Gain of ubiquitination at K582 (P = 0.0291)
MVP		0.37
MPC		1.3
ClinPred		0.19	T
GERP RS		4.9
Varity_R		0.19
gMVP		0.13
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: rs782476080; hg19: chrX-47835747; COSMIC: COSV100527209;