16-73694721-T-C

Variant names:

• chr16-73694721-T-C
• rs12920607
• NM_001386735.1:c.-1124-14481A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001386735.1(ZFHX3):​c.-1124-14481A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 152,120 control chromosomes in the GnomAD database, including 23,252 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 0.54 (23252 hom., cov: 33)
• Consequence: ZFHX3 NM_001386735.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.906
• Publications: 5 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.819 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386735.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX3	NM_001386735.1		c.-1124-14481A>G		intron	N/A	NP_001373664.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX3	ENST00000641206.2		c.-1607-14481A>G		intron	N/A	ENSP00000493252.1
	ZFHX3	ENST00000641018.1		n.101-14481A>G		intron	N/A
	ZFHX3	ENST00000642085.1		n.103-14481A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.536 AC: 81523 AN: 152002 Hom.: 23240 Cov.: 33

Gnomad AFR AF: 0.337

Gnomad AMI AF: 0.547

Gnomad AMR AF: 0.646

Gnomad ASJ AF: 0.683

Gnomad EAS AF: 0.840

Gnomad SAS AF: 0.629

Gnomad FIN AF: 0.626

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.580

Gnomad OTH AF: 0.560

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.536 AC: 81563 AN: 152120 Hom.: 23252 Cov.: 33 AF XY: 0.544 AC XY: 40489 AN XY: 74366

African (AFR) AF: 0.337 AC: 13995 AN: 41500

American (AMR) AF: 0.647 AC: 9886 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.683 AC: 2373 AN: 3472

East Asian (EAS) AF: 0.840 AC: 4338 AN: 5166

South Asian (SAS) AF: 0.627 AC: 3024 AN: 4820

European-Finnish (FIN) AF: 0.626 AC: 6612 AN: 10564

Middle Eastern (MID) AF: 0.677 AC: 199 AN: 294

European-Non Finnish (NFE) AF: 0.580 AC: 39442 AN: 67996

Other (OTH) AF: 0.566 AC: 1195 AN: 2112

Alfa AF: 0.577 Hom.: 113866

Bravo AF: 0.536

Asia WGS AF: 0.686 AC: 2384 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.81
DANN	Benign	0.80
PhyloP100		-0.91

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12920607; hg19: chr16-73728620;