chr8-123254647-C-T

Position:

chr8-123254647-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_007222.5(ZHX1):c.1300G>A(p.Ala434Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,614,126 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 2 hom. )

Consequence

ZHX1
NM_007222.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.230

Variant links:

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 links:

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]

ZHX1-C8orf76 links:

ZHX1 (HGNC:):

ZHX1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01231578).

BS2

High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZHX1	NM_007222.5 linkuse as main transcript	c.1300G>A	p.Ala434Thr	missense_variant	3/4	ENST00000395571.8	NP_009153.3	Q9UKY1-1A0A024R9F1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZHX1	ENST00000395571.8 linkuse as main transcript	c.1300G>A	p.Ala434Thr	missense_variant	3/4	1	NM_007222.5	ENSP00000378938.2		Q9UKY1-1
ZHX1-C8orf76	ENST00000357082.8 linkuse as main transcript	c.21+12626G>A		intron_variant		2		ENSP00000349593.4		Q96EF9-1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

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:

0.000176

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000143

AC:

AN:

251108

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135694

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000157

AC:

229

AN:

1461860

Hom.:

Cov.:

AF XY:

0.000157

AC XY:

114

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000181

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.000151

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000183

Hom.:

Bravo

AF:

0.000132

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2021

The c.1300G>A (p.A434T) alteration is located in exon 3 (coding exon 1) of the ZHX1 gene. This alteration results from a G to A substitution at nucleotide position 1300, causing the alanine (A) at amino acid position 434 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

0.064

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.61

CADD

Benign

2.4

DANN

Benign

0.72

DEOGEN2

Benign

0.017

T;T;T

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.64

T;.;.

M_CAP

Benign

0.0026

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.18

N;N;N

REVEL

Benign

0.016

Sift

Benign

0.63

T;T;T

Sift4G

Benign

0.46

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.059

MVP

0.24

MPC

0.26

ClinPred

0.018

GERP RS

0.064

Varity_R

0.031

gMVP

0.27

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over