Variant 16-72787435-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_006885.4(ZFHX3):c.10841G>C(p.Arg3614Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000268 in 1,453,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 27)

Exomes 𝑓: 0.0000098 ( 0 hom. )

Consequence

ZFHX3
NM_006885.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.924

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:

ZFHX3-AS1 (HGNC:):

ZFHX3-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09989783).

BS2

High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFHX3	NM_006885.4 linkuse as main transcript	c.10841G>C	p.Arg3614Thr	missense_variant	10/10	ENST00000268489.10	NP_008816.3	Q15911-1Q8N2Y6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFHX3	ENST00000268489.10 linkuse as main transcript	c.10841G>C	p.Arg3614Thr	missense_variant	10/10	1	NM_006885.4	ENSP00000268489.5		Q15911-1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

127410

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000569

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.00

Gnomad OTH

AF:

0.00114

GnomAD3 exomes

AF:

0.0000306

AC:

AN:

228950

Hom.:

AF XY:

0.0000240

AC XY:

AN XY:

125168

show subpopulations

Gnomad AFR exome

AF:

0.000427

Gnomad AMR exome

AF:

0.0000321

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000981

AC:

AN:

1325596

Hom.:

Cov.:

AF XY:

0.00000913

AC XY:

AN XY:

657354

show subpopulations

Gnomad4 AFR exome

AF:

0.000338

Gnomad4 AMR exome

AF:

0.0000505

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000194

GnomAD4 genome

AF:

0.000204

AC:

AN:

127410

Hom.:

Cov.:

AF XY:

0.000180

AC XY:

AN XY:

61188

show subpopulations

Gnomad4 AFR

AF:

0.000569

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00114

Alfa

AF:

0.0000676

Hom.:

Bravo

AF:

0.000200

ExAC

AF:

0.0000248

AC:

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

Sep 20, 2023

The c.10841G>C (p.R3614T) alteration is located in exon 10 (coding exon 9) of the ZFHX3 gene. This alteration results from a G to C substitution at nucleotide position 10841, causing the arginine (R) at amino acid position 3614 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

0.24

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

DANN

Benign

0.92

DEOGEN2

Benign

0.071

T;.;T

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.094

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.52

.;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.10

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.;L

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.37

N;N;.

REVEL

Benign

0.16

Sift

Benign

0.18

T;T;.

Sift4G

Benign

0.58

T;T;.

Polyphen

0.12

B;.;B

Vest4

0.20

MVP

0.093

MPC

0.14

ClinPred

0.055

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.41

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