X-47976834-A-G

Variant names:

• chrX-47976834-A-G
• rs1265919172
• NM_001007088.2:c.1196T>C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001007088.2(ZNF182):​c.1196T>C​(p.Ile399Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000058 in 1,207,490 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 2 hem.)
• Consequence: ZNF182 NM_001007088.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0440

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13283291).
• BS2: High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF182	NM_001007088.2	c.1196T>C	p.Ile399Thr	missense_variant	Exon 6 of 6	ENST00000376943.8	NP_001007089.1
ZNF182	NM_001178099.2	c.1253T>C	p.Ile418Thr	missense_variant	Exon 7 of 7		NP_001171570.1
ZNF182	NM_006962.2	c.1253T>C	p.Ile418Thr	missense_variant	Exon 7 of 7		NP_008893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF182	ENST00000376943.8	c.1196T>C	p.Ile399Thr	missense_variant	Exon 6 of 6	1	NM_001007088.2	ENSP00000366142.4
ZNF182	ENST00000396965.5	c.1253T>C	p.Ile418Thr	missense_variant	Exon 7 of 7	2		ENSP00000380165.1
ZNF81	ENST00000376950.4	c.278-25694A>G		intron_variant	Intron 4 of 4	5		ENSP00000366149.4

Frequencies

GnomAD3 genomes AF: 0.0000358 AC: 4 AN: 111817 Hom.: 0 Cov.: 23 AF XY: 0.0000588 AC XY: 2 AN XY: 34007

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000753

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 3 AN: 1095673 Hom.: 0 Cov.: 31 AF XY: 0.00000554 AC XY: 2 AN XY: 361217

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: 0.0000187

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000358 AC: 4 AN: 111817 Hom.: 0 Cov.: 23 AF XY: 0.0000588 AC XY: 2 AN XY: 34007

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000753

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1253T>C (p.I418T) alteration is located in exon 7 (coding exon 4) of the ZNF182 gene. This alteration results from a T to C substitution at nucleotide position 1253, causing the isoleucine (I) at amino acid position 418 to be replaced by a threonine (T). 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	0.14
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.030	.;T
FATHMM_MKL	Benign	0.00034	N
LIST_S2	Benign	0.17	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.31	.;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.073
Sift	Benign	0.34	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.062	.;B
Vest4		0.25
MutPred		0.36		.;Gain of disorder (P = 0.0243);
MVP		0.49
MPC		1.4
ClinPred		0.45	T
GERP RS		1.9
Varity_R		0.16
gMVP		0.12

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

Publications

LitVar

Other links and lift over

dbSNP: rs1265919172; hg19: chrX-47836233;