X-47976226-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001007088.2(ZNF182):​c.1804G>A​(p.Ala602Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000935 in 1,069,350 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. 14/21 in silico tools predict a benign outcome for this variant. 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. A602S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.4e-7 (0 hom. 0 hem.)
• Consequence: ZNF182 NM_001007088.2 missense
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059295803).

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>A	p.Ala602Thr	missense	Exon 6 of 6	NP_001007089.1	P17025-2
	ZNF182	NM_001178099.2		c.1861G>A	p.Ala621Thr	missense	Exon 7 of 7	NP_001171570.1	P17025-1
	ZNF182	NM_006962.2		c.1861G>A	p.Ala621Thr	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>A	p.Ala602Thr	missense	Exon 6 of 6	ENSP00000366142.4	P17025-2
	ZNF182	ENST00000396965.5	TSL:2	c.1861G>A	p.Ala621Thr	missense	Exon 7 of 7	ENSP00000380165.1	P17025-1
	ZNF182	ENST00000897864.1		c.1804G>A	p.Ala602Thr	missense	Exon 5 of 5	ENSP00000567923.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.35e-7 AC: 1 AN: 1069350 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 347220

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

American (AMR) AF: 0.00 AC: 0 AN: 29443

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17275

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 48196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39513

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

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 830958

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

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	5.3
DANN	Benign	0.86
DEOGEN2	Benign	0.0033	T
FATHMM_MKL	Benign	0.00030	N
LIST_S2	Benign	0.040	T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.72	N
PhyloP100		0.10
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	2.9	N
REVEL	Benign	0.045
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.46		Gain of phosphorylation at A621 (P = 0.0472)
MVP		0.15
MPC		0.40
ClinPred		0.046	T
GERP RS		1.1
Varity_R		0.039
gMVP		0.14
Mutation Taster		=97/3	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;