Variant 16-72787693-G-C 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.10583C>G(p.Ser3528Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000598 in 1,438,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000068 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

ZFHX3
NM_006885.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.19

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:56033): (ZFHX3 antisense RNA 1)

ZFHX3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21607322).

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFHX3	NM_006885.4 linkuse as main transcript	c.10583C>G	p.Ser3528Trp	missense_variant	10/10	ENST00000268489.10
ZFHX3-AS1	NR_171702.1 linkuse as main transcript	n.391-33080G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFHX3	ENST00000268489.10 linkuse as main transcript	c.10583C>G	p.Ser3528Trp	missense_variant	10/10	1	NM_006885.4	P1	Q15911-1
ZFHX3-AS1	ENST00000687589.1 linkuse as main transcript	n.482+5874G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000684

AC:

AN:

146116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000497

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000208

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000602

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000861

AC:

AN:

174288

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

97304

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000619

Gnomad SAS exome

AF:

0.000145

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000715

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000588

AC:

AN:

1292520

Hom.:

Cov.:

AF XY:

0.0000676

AC XY:

AN XY:

635682

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000323

Gnomad4 ASJ exome

AF:

0.0000460

Gnomad4 EAS exome

AF:

0.0000946

Gnomad4 SAS exome

AF:

0.000138

Gnomad4 FIN exome

AF:

0.0000223

Gnomad4 NFE exome

AF:

0.0000555

Gnomad4 OTH exome

AF:

0.000114

GnomAD4 genome

AF:

0.0000684

AC:

AN:

146116

Hom.:

Cov.:

AF XY:

0.0000846

AC XY:

AN XY:

70908

show subpopulations

Gnomad4 AFR

AF:

0.0000497

Gnomad4 AMR

AF:

0.000208

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000104

Gnomad4 NFE

AF:

0.0000602

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000945

ExAC

AF:

0.000108

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

Apr 25, 2022

The c.10583C>G (p.S3528W) alteration is located in exon 10 (coding exon 9) of the ZFHX3 gene. This alteration results from a C to G substitution at nucleotide position 10583, causing the serine (S) at amino acid position 3528 to be replaced by a tryptophan (W). 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

0.21

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Benign

0.94

DEOGEN2

Benign

0.14

T;.;T

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.90

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.22

T;T;T

MetaSVM

Benign

-0.37

MutationAssessor

Benign

1.4

L;.;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.4

N;N;.

REVEL

Uncertain

0.49

Sift

Uncertain

0.0050

D;D;.

Sift4G

Uncertain

0.014

D;D;.

Polyphen

0.89

P;.;P

Vest4

0.52

MutPred

0.31

Loss of disorder (P = 0.0071);.;Loss of disorder (P = 0.0071);

MVP

0.42

MPC

0.13

ClinPred

0.20

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.27

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