Variant 16-72958864-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_006885.4(ZFHX3):c.1282A>C(p.Thr428Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0306 in 1,613,332 control chromosomes in the GnomAD database, including 3,457 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.063 ( 673 hom., cov: 33)

Exomes 𝑓: 0.027 ( 2784 hom. )

Consequence

ZFHX3
NM_006885.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 4.37

Variant links:

Genes affected

ZFHX3 (HGNC:777): (zinc finger homeobox 3) This gene encodes a transcription factor with multiple homeodomains and zinc finger motifs, and regulates myogenic and neuronal differentiation. The encoded protein suppresses expression of the alpha-fetoprotein gene by binding to an AT-rich enhancer motif. The protein has also been shown to negatively regulate c-Myb, and transactivate the cell cycle inhibitor cyclin-dependent kinase inhibitor 1A (also known as p21CIP1). This gene is reported to function as a tumor suppressor in several cancers, and sequence variants of this gene are also associated with atrial fibrillation. Multiple transcript variants expressed from alternate promoters and encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

ZFHX3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014021397).

BP6

Variant 16-72958864-T-G is Benign according to our data. Variant chr16-72958864-T-G is described in ClinVar as [Benign]. Clinvar id is 3059393.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFHX3	NM_006885.4 linkuse as main transcript	c.1282A>C	p.Thr428Pro	missense_variant	2/10	ENST00000268489.10	NP_008816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFHX3	ENST00000268489.10 linkuse as main transcript	c.1282A>C	p.Thr428Pro	missense_variant	2/10	1	NM_006885.4	ENSP00000268489	P1	Q15911-1
ZFHX3	ENST00000397992.5 linkuse as main transcript	c.-23-7899A>C		intron_variant		1		ENSP00000438926		Q15911-2
ZFHX3	ENST00000641206.2 linkuse as main transcript	c.1282A>C	p.Thr428Pro	missense_variant	10/18			ENSP00000493252	P1	Q15911-1

Frequencies

GnomAD3 genomes

AF:

0.0626

AC:

9519

AN:

152010

Hom.:

665

Cov.:

show subpopulations

Gnomad AFR

AF:

0.109

Gnomad AMI

AF:

0.0198

Gnomad AMR

AF:

0.181

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.0826

Gnomad SAS

AF:

0.0330

Gnomad FIN

AF:

0.0656

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0116

Gnomad OTH

AF:

0.0585

GnomAD3 exomes

AF:

0.0714

AC:

17776

AN:

248982

Hom.:

1970

AF XY:

0.0601

AC XY:

8118

AN XY:

135146

show subpopulations

Gnomad AFR exome

AF:

0.108

Gnomad AMR exome

AF:

0.302

Gnomad ASJ exome

AF:

0.0121

Gnomad EAS exome

AF:

0.0841

Gnomad SAS exome

AF:

0.0336

Gnomad FIN exome

AF:

0.0603

Gnomad NFE exome

AF:

0.0119

Gnomad OTH exome

AF:

0.0566

GnomAD4 exome

AF:

0.0273

AC:

39868

AN:

1461206

Hom.:

2784

Cov.:

AF XY:

0.0261

AC XY:

18935

AN XY:

726796

show subpopulations

Gnomad4 AFR exome

AF:

0.111

Gnomad4 AMR exome

AF:

0.290

Gnomad4 ASJ exome

AF:

0.0110

Gnomad4 EAS exome

AF:

0.0832

Gnomad4 SAS exome

AF:

0.0334

Gnomad4 FIN exome

AF:

0.0566

Gnomad4 NFE exome

AF:

0.0104

Gnomad4 OTH exome

AF:

0.0336

GnomAD4 genome

AF:

0.0628

AC:

9548

AN:

152126

Hom.:

673

Cov.:

AF XY:

0.0671

AC XY:

4990

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.109

Gnomad4 AMR

AF:

0.182

Gnomad4 ASJ

AF:

0.0127

Gnomad4 EAS

AF:

0.0822

Gnomad4 SAS

AF:

0.0328

Gnomad4 FIN

AF:

0.0656

Gnomad4 NFE

AF:

0.0116

Gnomad4 OTH

AF:

0.0593

Alfa

AF:

0.0182

Hom.:

Bravo

AF:

0.0760

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.102

AC:

450

ESP6500EA

AF:

0.0118

AC:

101

ExAC

AF:

0.0614

AC:

7452

EpiCase

AF:

0.0122

EpiControl

AF:

0.0128

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

ZFHX3-related disorder

Benign:1

Benign, no assertion criteria provided

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

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.12

T;T

Eigen

Benign

-0.11

Eigen_PC

Benign

0.076

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.40

.;T

MetaRNN

Benign

0.0014

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

L;L

MutationTaster

Benign

0.000024

P;P

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.9

N;.

REVEL

Benign

0.15

Sift

Benign

0.10

T;.

Sift4G

Benign

0.13

T;.

Polyphen

0.017

B;B

Vest4

0.077

MPC

0.54

ClinPred

0.0098

GERP RS

4.9

Varity_R

0.30

gMVP

0.066

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