rs9921395

Variant names:

• chr16-72968058-G-A
• rs9921395
• NM_006885.4:c.-49-7864C>T

Variant summary

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

The NM_006885.4(ZFHX3):​c.-49-7864C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 151,186 control chromosomes in the GnomAD database, including 12,204 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 0.40 (12204 hom., cov: 29)
• Consequence: ZFHX3 NM_006885.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0600
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006885.4. 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_006885.4	MANE Select	c.-49-7864C>T		intron	N/A	NP_008816.3
	ZFHX3	NM_001386735.1		c.-49-7864C>T		intron	N/A	NP_001373664.1	Q15911-1
	ZFHX3	NM_001164766.2		c.-23-17093C>T		intron	N/A	NP_001158238.1	Q15911-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX3	ENST00000268489.10	TSL:1 MANE Select	c.-49-7864C>T		intron	N/A	ENSP00000268489.5	Q15911-1
	ZFHX3	ENST00000397992.5	TSL:1	c.-23-17093C>T		intron	N/A	ENSP00000438926.3	Q15911-2
	ZFHX3	ENST00000641206.2		c.-49-7864C>T		intron	N/A	ENSP00000493252.1	Q15911-1

Frequencies

GnomAD3 genomes AF: 0.396 AC: 59766 AN: 151078 Hom.: 12184 Cov.: 29

Gnomad AFR AF: 0.349

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.407

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.279

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.440

Gnomad OTH AF: 0.409

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

GnomAD4 genome AF: 0.396 AC: 59827 AN: 151186 Hom.: 12204 Cov.: 29 AF XY: 0.393 AC XY: 29031 AN XY: 73782

African (AFR) AF: 0.350 AC: 14389 AN: 41156

American (AMR) AF: 0.408 AC: 6199 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1387 AN: 3462

East Asian (EAS) AF: 0.121 AC: 623 AN: 5136

South Asian (SAS) AF: 0.280 AC: 1333 AN: 4768

European-Finnish (FIN) AF: 0.461 AC: 4768 AN: 10336

Middle Eastern (MID) AF: 0.381 AC: 109 AN: 286

European-Non Finnish (NFE) AF: 0.440 AC: 29818 AN: 67834

Other (OTH) AF: 0.405 AC: 847 AN: 2090

Alfa AF: 0.420 Hom.: 58661

Bravo AF: 0.392

Asia WGS AF: 0.185 AC: 647 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.0
DANN	Benign	0.70
PhyloP100		0.060
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs9921395; hg19: chr16-73001957;