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

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_024721.5(ZFHX4):c.196G>C(p.Val66Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0393 in 1,613,926 control chromosomes in the GnomAD database, including 1,459 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 Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V66I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.032 ( 108 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1351 hom. )

Consequence

ZFHX4
NM_024721.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001919806).

BP6

Variant 8-76704284-G-C is Benign according to our data. Variant chr8-76704284-G-C is described in ClinVar as [Benign]. Clinvar id is 3037425.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0317 (4829/152216) while in subpopulation NFE AF= 0.0459 (3125/68016). AF 95% confidence interval is 0.0446. There are 108 homozygotes in gnomad4. There are 2402 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 4829 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFHX4	NM_024721.5 linkuse as main transcript	c.196G>C	p.Val66Leu	missense_variant	2/11	ENST00000651372.2
ZFHX4	NM_001410934.1 linkuse as main transcript	c.196G>C	p.Val66Leu	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>C	p.Val66Leu	missense_variant	2/11		NM_024721.5	P4	Q86UP3-5

Frequencies

GnomAD3 genomes

AF:

0.0317

AC:

4828

AN:

152098

Hom.:

108

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00720

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.0319

Gnomad ASJ

AF:

0.0147

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.00622

Gnomad FIN

AF:

0.0689

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0459

Gnomad OTH

AF:

0.0283

GnomAD3 exomes

AF:

0.0317

AC:

7899

AN:

249086

Hom.:

184

AF XY:

0.0321

AC XY:

4335

AN XY:

135132

show subpopulations

Gnomad AFR exome

AF:

0.00620

Gnomad AMR exome

AF:

0.0184

Gnomad ASJ exome

AF:

0.0148

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00807

Gnomad FIN exome

AF:

0.0680

Gnomad NFE exome

AF:

0.0453

Gnomad OTH exome

AF:

0.0321

GnomAD4 exome

AF:

0.0401

AC:

58570

AN:

1461710

Hom.:

1351

Cov.:

AF XY:

0.0393

AC XY:

28564

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.00693

Gnomad4 AMR exome

AF:

0.0196

Gnomad4 ASJ exome

AF:

0.0167

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00776

Gnomad4 FIN exome

AF:

0.0642

Gnomad4 NFE exome

AF:

0.0458

Gnomad4 OTH exome

AF:

0.0316

GnomAD4 genome

AF:

0.0317

AC:

4829

AN:

152216

Hom.:

108

Cov.:

AF XY:

0.0323

AC XY:

2402

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.00717

Gnomad4 AMR

AF:

0.0318

Gnomad4 ASJ

AF:

0.0147

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.00623

Gnomad4 FIN

AF:

0.0689

Gnomad4 NFE

AF:

0.0459

Gnomad4 OTH

AF:

0.0280

Alfa

AF:

0.0343

Hom.:

Bravo

AF:

0.0272

TwinsUK

AF:

0.0448

AC:

166

ALSPAC

AF:

0.0431

AC:

166

ESP6500AA

AF:

0.00672

AC:

ESP6500EA

AF:

0.0389

AC:

329

ExAC

AF:

0.0315

AC:

3810

EpiCase

AF:

0.0417

EpiControl

AF:

0.0414

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

ZFHX4-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.60

CADD

Benign

1.9

DANN

Benign

0.68

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.69

T;.;T;T;T;T

MetaRNN

Benign

0.0019

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;.;.;.;.;.

MutationTaster

Benign

0.99

N;N;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.3

N;N;N;N;N;N

REVEL

Benign

0.041

Sift

Benign

0.049

D;T;T;T;T;D

Sift4G

Benign

0.29

T;T;D;T;T;T

Vest4

0.080

MPC

0.16

ClinPred

0.0055

GERP RS

-2.6

gMVP

0.15

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