Genetic Variant ZFHX3:n.557G>A (chr16-73679784-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000641018.1(ZFHX3):n.557G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.567 in 152,010 control chromosomes in the GnomAD database, including 25,797 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.57 ( 25797 hom., cov: 32)

Exomes 𝑓: 0.33 ( 0 hom. )

Consequence

ZFHX3
ENST00000641018.1 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.316

Publications

9 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.767 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFHX3	NM_001386735.1 link	c.-1064+396G>A		intron_variant	Intron 2 of 16		NP_001373664.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	Protein	UniProt
ZFHX3	ENST00000641018.1 link	n.557G>A	non_coding_transcript_exon_variant	Exon 2 of 2
ZFHX3	ENST00000641206.2 link	c.-1547+396G>A	intron_variant	Intron 2 of 17	ENSP00000493252.1	Q15911-1
ZFHX3	ENST00000642085.1 link	n.163+396G>A	intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.568

AC:

86243

AN:

151886

Hom.:

25798

Cov.:

show subpopulations

Gnomad AFR

AF:

0.361

Gnomad AMI

AF:

0.649

Gnomad AMR

AF:

0.652

Gnomad ASJ

AF:

0.784

Gnomad EAS

AF:

0.788

Gnomad SAS

AF:

0.674

Gnomad FIN

AF:

0.599

Gnomad MID

AF:

0.778

Gnomad NFE

AF:

0.631

Gnomad OTH

AF:

0.602

GnomAD4 exome

AF:

0.333

AC:

AN:

Hom.:

Cov.:

AF XY:

0.250

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.333

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.567

AC:

86262

AN:

152004

Hom.:

25797

Cov.:

AF XY:

0.569

AC XY:

42275

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.361

AC:

14955

AN:

41440

American (AMR)

AF:

0.652

AC:

9952

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.784

AC:

2722

AN:

3472

East Asian (EAS)

AF:

0.788

AC:

4069

AN:

5166

South Asian (SAS)

AF:

0.673

AC:

3245

AN:

4824

European-Finnish (FIN)

AF:

0.599

AC:

6315

AN:

10548

Middle Eastern (MID)

AF:

0.769

AC:

226

AN:

294

European-Non Finnish (NFE)

AF:

0.631

AC:

42909

AN:

67970

Other (OTH)

AF:

0.607

AC:

1280

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1803

3606

5409

7212

9015

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

740

1480

2220

2960

3700

<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:

0.617

Hom.:

79400

Bravo

AF:

0.569

Asia WGS

AF:

0.687

AC:

2390

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

5.3

(source)

DANN

Benign

0.38

PhyloP100

-0.32

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over