chrX-47976226-C-A

Variant names:

• chrX-47976226-C-A
• rs781802034
• NM_001007088.2:c.1804G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001007088.2(ZNF182):​c.1804G>T​(p.Ala602Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000892 in 112,121 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000037 (0 hom. 2 hem.)
  • Failed GnomAD Quality Control
• Consequence: ZNF182 NM_001007088.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.101
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08613497).

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.1804G>T	p.Ala602Ser	missense	Exon 6 of 6	NP_001007089.1	P17025-2
	ZNF182	NM_001178099.2		c.1861G>T	p.Ala621Ser	missense	Exon 7 of 7	NP_001171570.1	P17025-1
	ZNF182	NM_006962.2		c.1861G>T	p.Ala621Ser	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.1804G>T	p.Ala602Ser	missense	Exon 6 of 6	ENSP00000366142.4	P17025-2
	ZNF182	ENST00000396965.5	TSL:2	c.1861G>T	p.Ala621Ser	missense	Exon 7 of 7	ENSP00000380165.1	P17025-1
	ZNF182	ENST00000897864.1		c.1804G>T	p.Ala602Ser	missense	Exon 5 of 5	ENSP00000567923.1

Frequencies

GnomAD3 genomes AF: 0.00000892 AC: 1 AN: 112121 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000943

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000659 AC: 1 AN: 151855 AF XY: 0.0000208

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000468

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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00000374 AC: 4 AN: 1069341 Hom.: 0 Cov.: 31 AF XY: 0.00000576 AC XY: 2 AN XY: 347211

African (AFR) AF: 0.00 AC: 0 AN: 25088

American (AMR) AF: 0.0000679 AC: 2 AN: 29443

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17274

East Asian (EAS) AF: 0.00 AC: 0 AN: 30069

South Asian (SAS) AF: 0.00 AC: 0 AN: 48192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3985

European-Non Finnish (NFE) AF: 0.00000241 AC: 2 AN: 830955

Other (OTH) AF: 0.00 AC: 0 AN: 44823

GnomAD4 genome AF: 0.00000892 AC: 1 AN: 112121 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34281

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

African (AFR) AF: 0.00 AC: 0 AN: 30862

American (AMR) AF: 0.0000943 AC: 1 AN: 10604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3594

South Asian (SAS) AF: 0.00 AC: 0 AN: 2674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6083

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53218

Other (OTH) AF: 0.00 AC: 0 AN: 1508

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000330 AC: 4

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	Benign	0.078
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	15
DANN	Uncertain	0.97
DEOGEN2	Benign	0.0030	T
FATHMM_MKL	Benign	0.0049	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.17	N
PhyloP100		0.10
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.94	N
REVEL	Benign	0.034
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.046	D
Polyphen		0.0020	B
Vest4		0.12
MutPred		0.46		Gain of glycosylation at A621 (P = 0.0113)
MVP		0.15
MPC		0.38
ClinPred		0.075	T
GERP RS		1.1
Varity_R		0.078
gMVP		0.12
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: rs781802034; hg19: chrX-47835625;