8-123253371-T-C

Position:

• chr8-123253371-T-C

Variant summary

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

The NM_007222.5(ZHX1):​c.2576A>G​(p.Glu859Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZHX1 NM_007222.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.20

Genes affected

ZHX1 (HGNC:12871): (zinc fingers and homeoboxes 1) The members of the zinc fingers and homeoboxes gene family are nuclear homodimeric transcriptional repressors that interact with the A subunit of nuclear factor-Y (NF-YA) and contain two C2H2-type zinc fingers and five homeobox DNA-binding domains. This gene encodes member 1 of this gene family. In addition to forming homodimers, this protein heterodimerizes with members 2 and 3 of the zinc fingers and homeoboxes family. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream chromosome 8 open reading frame 76 (C8orf76) gene. [provided by RefSeq, Feb 2011]

ZHX1-C8orf76 (HGNC:42975): (ZHX1-C8orf76 readthrough) This locus represents naturally occurring read-through transcription between the neighboring zinc fingers and homeoboxes 1 (ZHX1) and chromosome 8 open reading frame 76 (C8orf76) genes. The read-through transcript encodes a protein that shares sequence identity with the downstream gene, but it has a distinct N-terminus encoded by exon structure from the upstream gene. [provided by RefSeq, Feb 2011]

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=0.34831816).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZHX1	NM_007222.5	c.2576A>G	p.Glu859Gly	missense_variant	3/4	ENST00000395571.8	NP_009153.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZHX1	ENST00000395571.8	c.2576A>G	p.Glu859Gly	missense_variant	3/4	1	NM_007222.5	ENSP00000378938.2
ZHX1-C8orf76	ENST00000357082.8	c.21+13902A>G		intron_variant		2		ENSP00000349593.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2024

The c.2576A>G (p.E859G) alteration is located in exon 3 (coding exon 1) of the ZHX1 gene. This alteration results from a A to G substitution at nucleotide position 2576, causing the glutamic acid (E) at amino acid position 859 to be replaced by a glycine (G). 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	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.069	T;T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;.;.
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	0.81	L;L;L
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.71
MutPred		0.12		Gain of MoRF binding (P = 0.0613);Gain of MoRF binding (P = 0.0613);Gain of MoRF binding (P = 0.0613);
MVP		0.22
MPC		1.0
ClinPred		0.91	D
GERP RS		6.0
Varity_R		0.32
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-124265611;