chr16-73770802-C-T

Variant names:

• chr16-73770802-C-T
• rs16972539
• NM_001386735.1:c.-1124-90562G>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.-1124-90562G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 152,172 control chromosomes in the GnomAD database, including 2,460 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 0.17 (2460 hom., cov: 33)
• Consequence: ZFHX3 NM_001386735.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0270
• Publications: 6 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

ENSG00000303711 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.406 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX3	NM_001386735.1		c.-1124-90562G>A		intron	N/A	NP_001373664.1	Q15911-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX3	ENST00000641206.2		c.-1607-90562G>A		intron	N/A	ENSP00000493252.1	Q15911-1
	ZFHX3	ENST00000641018.1		n.101-90562G>A		intron	N/A
	ZFHX3	ENST00000642085.1		n.103-90562G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25427 AN: 152052 Hom.: 2460 Cov.: 33

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.178

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.421

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.0941

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.179

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

GnomAD4 genome AF: 0.167 AC: 25442 AN: 152172 Hom.: 2460 Cov.: 33 AF XY: 0.170 AC XY: 12681 AN XY: 74396

African (AFR) AF: 0.184 AC: 7650 AN: 41504

American (AMR) AF: 0.188 AC: 2878 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 555 AN: 3470

East Asian (EAS) AF: 0.421 AC: 2166 AN: 5150

South Asian (SAS) AF: 0.289 AC: 1394 AN: 4818

European-Finnish (FIN) AF: 0.0941 AC: 998 AN: 10606

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.135 AC: 9197 AN: 68014

Other (OTH) AF: 0.182 AC: 384 AN: 2114

Alfa AF: 0.152 Hom.: 6364

Bravo AF: 0.179

Asia WGS AF: 0.341 AC: 1186 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	9.0
DANN	Benign	0.65
PhyloP100		-0.027

Splicing

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

Other links and lift over

dbSNP: rs16972539; hg19: chr16-73804701;