20-41202411-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001384317.1(ZHX3):c.2506C>G(p.Pro836Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZHX3 NM_001384317.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.93

Genes affected

ZHX3 (HGNC:15935): (zinc fingers and homeoboxes 3) This gene encodes a member of the zinc fingers and homeoboxes (ZHX) gene family. The encoded protein contains two C2H2-type zinc fingers and five homeodomains and forms a dimer with itself or with zinc fingers and homeoboxes family member 1. In the nucleus, the dimerized protein interacts with the A subunit of the ubiquitous transcription factor nuclear factor-Y and may function as a transcriptional repressor. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26922584).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZHX3	NM_001384317.1	c.2506C>G	p.Pro836Ala	missense_variant	3/4	ENST00000683867.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZHX3	ENST00000683867.1	c.2506C>G	p.Pro836Ala	missense_variant	3/4		NM_001384317.1	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461862 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with ZHX3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 836 of the ZHX3 protein (p.Pro836Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	22
Dann	Benign	0.89
DEOGEN2	Benign	0.014	T;T;.;T;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.27	T;T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.1	M;M;M;M;M
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Benign	0.43	T
REVEL	Benign	0.15
Sift4G	Benign	0.81	T;T;T;T;T
Polyphen		0.23	B;B;.;B;B
Vest4		0.41
MutPred		0.42		Loss of ubiquitination at K831 (P = 0.1151);Loss of ubiquitination at K831 (P = 0.1151);Loss of ubiquitination at K831 (P = 0.1151);Loss of ubiquitination at K831 (P = 0.1151);Loss of ubiquitination at K831 (P = 0.1151);
MVP		0.35
MPC		0.52
ClinPred		0.29	T
GERP RS		6.1
Varity_R		0.073
gMVP		0.17

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: rs2038305158; hg19: chr20-39831051;