rs11648088

Variant names:

• chr16-73505482-A-G
• rs11648088
• NM_001386735.1:c.-1063-49224T>C

Variant summary

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

The NM_001386735.1(ZFHX3):​c.-1063-49224T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 151,802 control chromosomes in the GnomAD database, including 6,203 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 0.25 (6203 hom., cov: 30)
• Consequence: ZFHX3 NM_001386735.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0580
• Publications: 0 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=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.358 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.-1063-49224T>C		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.-1546-49224T>C		intron	N/A	ENSP00000493252.1	Q15911-1

Frequencies

GnomAD3 genomes AF: 0.251 AC: 38094 AN: 151684 Hom.: 6201 Cov.: 30

Gnomad AFR AF: 0.0876

Gnomad AMI AF: 0.342

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.00386

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.260

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

GnomAD4 genome AF: 0.251 AC: 38095 AN: 151802 Hom.: 6203 Cov.: 30 AF XY: 0.248 AC XY: 18432 AN XY: 74174

African (AFR) AF: 0.0876 AC: 3627 AN: 41426

American (AMR) AF: 0.197 AC: 3005 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1053 AN: 3468

East Asian (EAS) AF: 0.00387 AC: 20 AN: 5170

South Asian (SAS) AF: 0.116 AC: 559 AN: 4800

European-Finnish (FIN) AF: 0.413 AC: 4329 AN: 10484

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.362 AC: 24577 AN: 67902

Other (OTH) AF: 0.258 AC: 541 AN: 2100

Alfa AF: 0.304 Hom.: 12797

Bravo AF: 0.230

Asia WGS AF: 0.0670 AC: 237 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.8
DANN	Benign	0.58
PhyloP100		-0.058

Splicing

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

Other links and lift over

dbSNP: rs11648088; hg19: chr16-73539381;