rs16972369

Variant names:

• chr16-73719083-A-G
• rs16972369
• NM_001386735.1:c.-1124-38843T>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.-1124-38843T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0796 in 152,216 control chromosomes in the GnomAD database, including 767 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 0.080 (767 hom., cov: 33)
• Consequence: ZFHX3 NM_001386735.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.339
• Publications: 2 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFHX3	NM_001386735.1	c.-1124-38843T>C		intron_variant	Intron 1 of 16		NP_001373664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFHX3	ENST00000641206.2	c.-1607-38843T>C		intron_variant	Intron 1 of 17			ENSP00000493252.1
ZFHX3	ENST00000641018.1	n.101-38843T>C		intron_variant	Intron 1 of 1
ZFHX3	ENST00000642085.1	n.103-38843T>C		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.0795 AC: 12089 AN: 152098 Hom.: 765 Cov.: 33

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0421

Gnomad ASJ AF: 0.0351

Gnomad EAS AF: 0.0156

Gnomad SAS AF: 0.0438

Gnomad FIN AF: 0.0268

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0507

Gnomad OTH AF: 0.0603

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

GnomAD4 genome AF: 0.0796 AC: 12110 AN: 152216 Hom.: 767 Cov.: 33 AF XY: 0.0767 AC XY: 5707 AN XY: 74410

African (AFR) AF: 0.171 AC: 7110 AN: 41518

American (AMR) AF: 0.0421 AC: 643 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0351 AC: 122 AN: 3472

East Asian (EAS) AF: 0.0157 AC: 81 AN: 5168

South Asian (SAS) AF: 0.0442 AC: 213 AN: 4818

European-Finnish (FIN) AF: 0.0268 AC: 285 AN: 10616

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0507 AC: 3447 AN: 68022

Other (OTH) AF: 0.0588 AC: 124 AN: 2110

Alfa AF: 0.0583 Hom.: 193

Bravo AF: 0.0842

Asia WGS AF: 0.0340 AC: 119 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.6
DANN	Benign	0.47
PhyloP100		0.34

Splicing

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

Other links and lift over

dbSNP: rs16972369; hg19: chr16-73752982;