rs782476080

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-47976348-C-G
• chrX-47976348-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001007088.2(ZNF182):​c.1682G>C​(p.Arg561Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000914 in 1,093,984 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R561Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: ZNF182 NM_001007088.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.589
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>C	p.Arg561Pro	missense	Exon 6 of 6	NP_001007089.1	P17025-2
	ZNF182	NM_001178099.2		c.1739G>C	p.Arg580Pro	missense	Exon 7 of 7	NP_001171570.1	P17025-1
	ZNF182	NM_006962.2		c.1739G>C	p.Arg580Pro	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>C	p.Arg561Pro	missense	Exon 6 of 6	ENSP00000366142.4	P17025-2
	ZNF182	ENST00000396965.5	TSL:2	c.1739G>C	p.Arg580Pro	missense	Exon 7 of 7	ENSP00000380165.1	P17025-1
	ZNF182	ENST00000897864.1		c.1682G>C	p.Arg561Pro	missense	Exon 5 of 5	ENSP00000567923.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1093984 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 359864

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 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: 0.00000119 AC: 1 AN: 840416

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.028	T
FATHMM_MKL	Benign	0.00023	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0088	T
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.11	N
PhyloP100		-0.59
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.18
Sift	Benign	0.095	T
Sift4G	Benign	0.20	T
Polyphen		0.99	D
Vest4		0.56
MutPred		0.50		Loss of catalytic residue at R580 (P = 0.0079)
MVP		0.57
MPC		1.5
ClinPred		0.88	D
GERP RS		4.9
Varity_R		0.66
gMVP		0.55
Mutation Taster		=91/9	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;