chr16-72959932-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_006885.4(ZFHX3):c.214T>G(p.Ser72Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.411 in 1,596,348 control chromosomes in the GnomAD database, including 140,363 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Synonymous variant affecting the same amino acid position (i.e. S72S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.48 ( 18891 hom., cov: 32)

Exomes 𝑓: 0.40 ( 121472 hom. )

Consequence

ZFHX3
NM_006885.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.63

Publications

35 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
syndromic complex neurodevelopmental disorder
Inheritance: AD Classification: STRONG Submitted by: Broad Center for Mendelian Genomics
spinocerebellar ataxia type 4
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
epilepsy
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ZFHX3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.6056085E-6).

BP6

Variant 16-72959932-A-C is Benign according to our data. Variant chr16-72959932-A-C is described in ClinVar as Benign. ClinVar VariationId is 3060596.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.695 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFHX3	NM_006885.4 link	c.214T>G	p.Ser72Ala	missense_variant	Exon 2 of 10	ENST00000268489.10	NP_008816.3	Q15911-1Q8N2Y6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZFHX3	ENST00000268489.10 link	c.214T>G	p.Ser72Ala	missense_variant	Exon 2 of 10	1	NM_006885.4	ENSP00000268489.5	Q15911-1
ZFHX3	ENST00000397992.5 link	c.-23-8967T>G		intron_variant	Intron 1 of 8	1		ENSP00000438926.3	Q15911-2
ZFHX3	ENST00000641206.2 link	c.214T>G	p.Ser72Ala	missense_variant	Exon 10 of 18			ENSP00000493252.1	Q15911-1

Frequencies

GnomAD3 genomes

AF:

0.476

AC:

72249

AN:

151772

Hom.:

18856

Cov.:

show subpopulations

Gnomad AFR

AF:

0.701

Gnomad AMI

AF:

0.377

Gnomad AMR

AF:

0.316

Gnomad ASJ

AF:

0.357

Gnomad EAS

AF:

0.260

Gnomad SAS

AF:

0.457

Gnomad FIN

AF:

0.467

Gnomad MID

AF:

0.366

Gnomad NFE

AF:

0.404

Gnomad OTH

AF:

0.425

GnomAD2 exomes

AF:

0.387

AC:

87536

AN:

225974

AF XY:

0.390

show subpopulations

Gnomad AFR exome

AF:

0.700

Gnomad AMR exome

AF:

0.222

Gnomad ASJ exome

AF:

0.328

Gnomad EAS exome

AF:

0.265

Gnomad FIN exome

AF:

0.447

Gnomad NFE exome

AF:

0.395

Gnomad OTH exome

AF:

0.368

GnomAD4 exome

AF:

0.404

AC:

583292

AN:

1444458

Hom.:

121472

Cov.:

AF XY:

0.405

AC XY:

290190

AN XY:

716784

show subpopulations

African (AFR)

AF:

0.713

AC:

23604

AN:

33094

American (AMR)

AF:

0.238

AC:

10225

AN:

43018

Ashkenazi Jewish (ASJ)

AF:

0.336

AC:

8453

AN:

25142

East Asian (EAS)

AF:

0.239

AC:

9412

AN:

39314

South Asian (SAS)

AF:

0.454

AC:

38142

AN:

83948

European-Finnish (FIN)

AF:

0.462

AC:

23989

AN:

51972

Middle Eastern (MID)

AF:

0.363

AC:

2063

AN:

5688

European-Non Finnish (NFE)

AF:

0.402

AC:

442883

AN:

1102712

Other (OTH)

AF:

0.412

AC:

24521

AN:

59570

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

23099

46198

69296

92395

115494

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13910

27820

41730

55640

69550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.476

AC:

72335

AN:

151890

Hom.:

18891

Cov.:

AF XY:

0.472

AC XY:

35022

AN XY:

74240

show subpopulations

African (AFR)

AF:

0.701

AC:

29060

AN:

41436

American (AMR)

AF:

0.316

AC:

4826

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.357

AC:

1237

AN:

3468

East Asian (EAS)

AF:

0.260

AC:

1328

AN:

5116

South Asian (SAS)

AF:

0.457

AC:

2186

AN:

4788

European-Finnish (FIN)

AF:

0.467

AC:

4945

AN:

10582

Middle Eastern (MID)

AF:

0.346

AC:

101

AN:

292

European-Non Finnish (NFE)

AF:

0.404

AC:

27414

AN:

67926

Other (OTH)

AF:

0.427

AC:

896

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1818

3636

5455

7273

9091

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

638

1276

1914

2552

3190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.395

Hom.:

17708

Bravo

AF:

0.470

TwinsUK

AF:

0.396

AC:

1470

ALSPAC

AF:

0.407

AC:

1567

ESP6500AA

AF:

0.676

AC:

2955

ESP6500EA

AF:

0.371

AC:

3183

ExAC

AF:

0.365

AC:

43062

Asia WGS

AF:

0.397

AC:

1375

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

ZFHX3-related disorder

Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

0.051

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.50

CADD

Benign

8.1

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.091

T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.060

.;T

MetaRNN

Benign

0.0000036

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.34

N;N

PhyloP100

1.6

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.44

N;.

REVEL

Benign

0.21

Sift

Benign

1.0

T;.

Sift4G

Benign

0.61

T;.

Polyphen

0.0060

B;B

Vest4

0.030

MPC

0.078

ClinPred

0.0057

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.088

gMVP

0.035

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over