X-47977557-C-T

Variant names:

• chrX-47977557-C-T
• rs782325713
• NM_001007088.2:c.473G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001007088.2(ZNF182):​c.473G>A​(p.Ser158Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000366 in 1,093,758 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 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: 0.0000037 (0 hom. 1 hem.)
• Consequence: ZNF182 NM_001007088.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.172

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052458376).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF182	NM_001007088.2	c.473G>A	p.Ser158Asn	missense_variant	Exon 6 of 6	ENST00000376943.8	NP_001007089.1
ZNF182	NM_001178099.2	c.530G>A	p.Ser177Asn	missense_variant	Exon 7 of 7		NP_001171570.1
ZNF182	NM_006962.2	c.530G>A	p.Ser177Asn	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.473G>A	p.Ser158Asn	missense_variant	Exon 6 of 6	1	NM_001007088.2	ENSP00000366142.4
ZNF182	ENST00000396965.5	c.530G>A	p.Ser177Asn	missense_variant	Exon 7 of 7	2		ENSP00000380165.1
ZNF81	ENST00000376950.4	c.278-24971C>T		intron_variant	Intron 4 of 4	5		ENSP00000366149.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000170 AC: 3 AN: 176520 Hom.: 0 AF XY: 0.0000162 AC XY: 1 AN XY: 61772

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000220

Gnomad SAS 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: 0.00000366 AC: 4 AN: 1093758 Hom.: 0 Cov.: 30 AF XY: 0.00000278 AC XY: 1 AN XY: 359766

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000133

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.530G>A (p.S177N) alteration is located in exon 7 (coding exon 4) of the ZNF182 gene. This alteration results from a G to A substitution at nucleotide position 530, causing the serine (S) at amino acid position 177 to be replaced by an asparagine (N). 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	0.073
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	1.7
DANN	Benign	0.81
DEOGEN2	Benign	0.0079	.;T
FATHMM_MKL	Benign	0.00053	N
LIST_S2	Benign	0.023	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.052	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.54	.;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.24	N;N
REVEL	Benign	0.030
Sift	Benign	0.63	T;T
Sift4G	Benign	0.50	T;T
Polyphen		0.0010	.;B
Vest4		0.13
MutPred		0.41		.;Loss of phosphorylation at S177 (P = 0.0959);
MVP		0.24
MPC		0.38
ClinPred		0.013	T
GERP RS		1.5
Varity_R		0.056
gMVP		0.19

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: rs782325713; hg19: chrX-47836956;