rs963234149

Variant names:

• chr20-41202108-C-A
• rs963234149
• NM_001384317.1:c.2809G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001384317.1(ZHX3):​c.2809G>T​(p.Ala937Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,098 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: 0.0000027 (0 hom.)
• Consequence: ZHX3 NM_001384317.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.23

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08103907).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZHX3	NM_001384317.1	c.2809G>T	p.Ala937Ser	missense_variant	Exon 3 of 4	ENST00000683867.1	NP_001371246.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZHX3	ENST00000683867.1	c.2809G>T	p.Ala937Ser	missense_variant	Exon 3 of 4		NM_001384317.1	ENSP00000506788.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461098 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726784

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 937 of the ZHX3 protein (p.Ala937Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ZHX3-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0035	T;T;T;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.75	.;.;.;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.081	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;M;M
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.32	.;N;N;.
REVEL	Benign	0.079
Sift	Benign	0.11	.;T;T;.
Sift4G	Benign	0.52	T;T;T;T
Polyphen		0.36	B;B;B;B
Vest4		0.20
MutPred		0.098		Gain of phosphorylation at A937 (P = 0.0052);Gain of phosphorylation at A937 (P = 0.0052);Gain of phosphorylation at A937 (P = 0.0052);Gain of phosphorylation at A937 (P = 0.0052);
MVP		0.30
MPC		0.26
ClinPred		0.30	T
GERP RS		4.9
Varity_R		0.084
gMVP		0.072

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: rs963234149; hg19: chr20-39830748;