8-123254622-G-A

Position:

chr8-123254622-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_007222.5(ZHX1):c.1325C>T(p.Pro442Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00073 in 1,614,126 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00038 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00077 ( 0 hom. )

Consequence

ZHX1
NM_007222.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.45

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:):

ZHX1-C8orf76 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.02784568).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZHX1	NM_007222.5 linkuse as main transcript	c.1325C>T	p.Pro442Leu	missense_variant	3/4	ENST00000395571.8	NP_009153.3
ZHX1-C8orf76	NM_001204180.2 linkuse as main transcript	c.21+12651C>T		intron_variant			NP_001191109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZHX1	ENST00000395571.8 linkuse as main transcript	c.1325C>T	p.Pro442Leu	missense_variant	3/4	1	NM_007222.5	ENSP00000378938	P1	Q9UKY1-1
ZHX1	ENST00000297857.3 linkuse as main transcript	c.1325C>T	p.Pro442Leu	missense_variant	3/4	5		ENSP00000297857	P1	Q9UKY1-1
ZHX1	ENST00000522655.5 linkuse as main transcript	c.1325C>T	p.Pro442Leu	missense_variant	3/4	2		ENSP00000428821	P1	Q9UKY1-1
ZHX1	ENST00000517516.1 linkuse as main transcript	n.120-4302C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000227

AC:

AN:

251106

Hom.:

AF XY:

0.000192

AC XY:

AN XY:

135704

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000458

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000766

AC:

1120

AN:

1461866

Hom.:

Cov.:

AF XY:

0.000700

AC XY:

509

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000224

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:

0.000960

Gnomad4 OTH exome

AF:

0.000729

GnomAD4 genome

AF:

0.000381

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000647

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000588

Hom.:

Bravo

AF:

0.000487

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000255

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000593

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

Feb 26, 2024

The c.1325C>T (p.P442L) alteration is located in exon 3 (coding exon 1) of the ZHX1 gene. This alteration results from a C to T substitution at nucleotide position 1325, causing the proline (P) at amino acid position 442 to be replaced by a leucine (L). 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

0.067

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.71

DEOGEN2

Benign

0.030

T;T;T

Eigen

Benign

0.060

Eigen_PC

Benign

0.082

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.80

T;.;.

M_CAP

Benign

0.0099

MetaRNN

Benign

0.028

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.69

N;N;N

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.61

N;N;N

REVEL

Benign

0.039

Sift

Benign

0.091

T;T;T

Sift4G

Benign

0.083

T;T;T

Polyphen

0.12

B;B;B

Vest4

0.16

MVP

0.27

MPC

0.27

ClinPred

0.048

GERP RS

4.0

Varity_R

0.042

gMVP

0.24

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