rs4887870

Variant names:

• chr16-73616954-A-G
• rs4887870
• NM_001386735.1:c.-1064+63226T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BA1

The NM_001386735.1(ZFHX3):​c.-1064+63226T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 152,066 control chromosomes in the GnomAD database, including 7,151 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 0.28 (7151 hom., cov: 30)
• Consequence: ZFHX3 NM_001386735.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.31
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.17).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.466 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.-1064+63226T>C		intron	N/A	NP_001373664.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX3	ENST00000641206.2		c.-1547+63226T>C		intron	N/A	ENSP00000493252.1
	ZFHX3	ENST00000642085.1		n.164-6859T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42486 AN: 151948 Hom.: 7142 Cov.: 30

Gnomad AFR AF: 0.472

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.244

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

GnomAD4 genome AF: 0.280 AC: 42555 AN: 152066 Hom.: 7151 Cov.: 30 AF XY: 0.280 AC XY: 20820 AN XY: 74318

African (AFR) AF: 0.472 AC: 19547 AN: 41450

American (AMR) AF: 0.217 AC: 3321 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 366 AN: 3464

East Asian (EAS) AF: 0.174 AC: 900 AN: 5162

South Asian (SAS) AF: 0.221 AC: 1066 AN: 4816

European-Finnish (FIN) AF: 0.276 AC: 2921 AN: 10588

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.201 AC: 13680 AN: 67986

Other (OTH) AF: 0.248 AC: 522 AN: 2108

Alfa AF: 0.214 Hom.: 17395

Bravo AF: 0.278

Asia WGS AF: 0.223 AC: 774 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Benign	0.75
PhyloP100		3.3

Splicing

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

Other links and lift over

dbSNP: rs4887870; hg19: chr16-73650853;