16-73547159-A-G

Variant names:

• chr16-73547159-A-G
• rs7191888
• NM_001386735.1:c.-1063-90901T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001386735.1(ZFHX3):​c.-1063-90901T>C variant causes a intron change. The variant allele was found at a frequency of 0.223 in 151,920 control chromosomes in the GnomAD database, including 4,152 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 (4152 hom., cov: 31)
• Consequence: ZFHX3 NM_001386735.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.77
• Publications: 14 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

ENSG00000260848 (HGNC:58537):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFHX3	NM_001386735.1	c.-1063-90901T>C		intron_variant	Intron 2 of 16		NP_001373664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFHX3	ENST00000641206.2	c.-1546-90901T>C		intron_variant	Intron 2 of 17			ENSP00000493252.1
ENSG00000260848	ENST00000567227.1	n.68+3151A>G		intron_variant	Intron 1 of 3	4
ENSG00000260848	ENST00000658533.1	n.112+802A>G		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes AF: 0.223 AC: 33780 AN: 151802 Hom.: 4130 Cov.: 31

Gnomad AFR AF: 0.336

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.180

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.198

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

GnomAD4 genome AF: 0.223 AC: 33849 AN: 151920 Hom.: 4152 Cov.: 31 AF XY: 0.222 AC XY: 16456 AN XY: 74274

African (AFR) AF: 0.336 AC: 13929 AN: 41410

American (AMR) AF: 0.192 AC: 2931 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 595 AN: 3466

East Asian (EAS) AF: 0.123 AC: 633 AN: 5166

South Asian (SAS) AF: 0.189 AC: 910 AN: 4804

European-Finnish (FIN) AF: 0.180 AC: 1901 AN: 10568

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.182 AC: 12352 AN: 67926

Other (OTH) AF: 0.203 AC: 429 AN: 2110

Alfa AF: 0.193 Hom.: 8435

Bravo AF: 0.230

Asia WGS AF: 0.194 AC: 675 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Benign	0.82
PhyloP100		3.8

Splicing

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

Other links and lift over

dbSNP: rs7191888; hg19: chr16-73581058;