16-73739604-G-T

Variant names:

• chr16-73739604-G-T
• rs4888688
• NM_001386735.1:c.-1124-59364C>A

Variant summary

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

The NM_001386735.1(ZFHX3):​c.-1124-59364C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 152,086 control chromosomes in the GnomAD database, including 4,606 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 0.22 (4606 hom., cov: 32)
• Consequence: ZFHX3 NM_001386735.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.350
• Publications: 3 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=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.308 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.-1124-59364C>A		intron	N/A	NP_001373664.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX3	ENST00000641206.2		c.-1607-59364C>A		intron	N/A	ENSP00000493252.1
	ZFHX3	ENST00000641018.1		n.101-59364C>A		intron	N/A
	ZFHX3	ENST00000642085.1		n.103-59364C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33649 AN: 151968 Hom.: 4606 Cov.: 32

Gnomad AFR AF: 0.0589

Gnomad AMI AF: 0.264

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.221

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

GnomAD4 genome AF: 0.221 AC: 33642 AN: 152086 Hom.: 4606 Cov.: 32 AF XY: 0.219 AC XY: 16269 AN XY: 74340

African (AFR) AF: 0.0588 AC: 2443 AN: 41560

American (AMR) AF: 0.200 AC: 3059 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 996 AN: 3470

East Asian (EAS) AF: 0.145 AC: 749 AN: 5170

South Asian (SAS) AF: 0.234 AC: 1129 AN: 4820

European-Finnish (FIN) AF: 0.317 AC: 3347 AN: 10556

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.311 AC: 21158 AN: 67930

Other (OTH) AF: 0.218 AC: 460 AN: 2112

Alfa AF: 0.272 Hom.: 11219

Bravo AF: 0.204

Asia WGS AF: 0.156 AC: 542 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.0
DANN	Benign	0.55
PhyloP100		-0.35

Splicing

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

Other links and lift over

dbSNP: rs4888688; hg19: chr16-73773503;