Variant chr8-76704284-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_024721.5(ZFHX4):c.196G>A(p.Val66Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,613,928 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V66L) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0037 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 41 hom. )

Consequence

ZFHX4
NM_024721.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.188

Variant links:

Genes affected

ZFHX4 (HGNC:30939): (zinc finger homeobox 4) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZFHX4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003713876).

BP6

Variant 8-76704284-G-A is Benign according to our data. Variant chr8-76704284-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2658657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 557 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFHX4	NM_024721.5 linkuse as main transcript	c.196G>A	p.Val66Ile	missense_variant	2/11	ENST00000651372.2
ZFHX4	NM_001410934.1 linkuse as main transcript	c.196G>A	p.Val66Ile	missense_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFHX4	ENST00000651372.2 linkuse as main transcript	c.196G>A	p.Val66Ile	missense_variant	2/11		NM_024721.5	P4	Q86UP3-5

Frequencies

GnomAD3 genomes

AF:

0.00366

AC:

557

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0252

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00384

Gnomad OTH

AF:

0.00384

GnomAD3 exomes

AF:

0.00405

AC:

1009

AN:

249086

Hom.:

AF XY:

0.00390

AC XY:

527

AN XY:

135132

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0260

Gnomad NFE exome

AF:

0.00360

Gnomad OTH exome

AF:

0.00529

GnomAD4 exome

AF:

0.00222

AC:

3251

AN:

1461710

Hom.:

Cov.:

AF XY:

0.00228

AC XY:

1659

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0257

Gnomad4 NFE exome

AF:

0.00154

Gnomad4 OTH exome

AF:

0.00237

GnomAD4 genome

AF:

0.00366

AC:

557

AN:

152218

Hom.:

Cov.:

AF XY:

0.00454

AC XY:

338

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0252

Gnomad4 NFE

AF:

0.00384

Gnomad4 OTH

AF:

0.00380

Alfa

AF:

0.00137

Hom.:

Bravo

AF:

0.00107

ExAC

AF:

0.00393

AC:

475

EpiCase

AF:

0.00234

EpiControl

AF:

0.00130

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

ZFHX4-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

ZFHX4: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.64

CADD

Benign

2.2

DANN

Benign

0.71

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.67

T;.;T;T;T;T

MetaRNN

Benign

0.0037

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.;.;.;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.56

N;N;N;N;N;N

REVEL

Benign

0.039

Sift

Benign

0.42

T;T;T;T;T;T

Sift4G

Benign

0.51

T;T;T;T;T;T

Vest4

0.062

MVP

0.082

MPC

0.13

ClinPred

0.013

GERP RS

-2.6

gMVP

0.087

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