rs328384

Variant names:

• chr16-73805897-G-A
• rs328384
• NM_001386735.1:c.-1125+85754C>T

Variant summary

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

The NM_001386735.1(ZFHX3):​c.-1125+85754C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 152,036 control chromosomes in the GnomAD database, including 12,151 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 0.39 (12151 hom., cov: 32)
• Consequence: ZFHX3 NM_001386735.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0670
• Publications: 6 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

ENSG00000283457 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.492 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.-1125+85754C>T		intron	N/A	NP_001373664.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX3	ENST00000641206.2		c.-1608+85754C>T		intron	N/A	ENSP00000493252.1
	ENSG00000283457	ENST00000637695.1	TSL:5	n.425-2575G>A		intron	N/A
	ZFHX3	ENST00000641018.1		n.100+85754C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.394 AC: 59813 AN: 151916 Hom.: 12135 Cov.: 32

Gnomad AFR AF: 0.498

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.345

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.492

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.363

Gnomad NFE AF: 0.352

Gnomad OTH AF: 0.397

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

GnomAD4 genome AF: 0.394 AC: 59876 AN: 152036 Hom.: 12151 Cov.: 32 AF XY: 0.393 AC XY: 29190 AN XY: 74312

African (AFR) AF: 0.498 AC: 20643 AN: 41466

American (AMR) AF: 0.344 AC: 5262 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 1109 AN: 3470

East Asian (EAS) AF: 0.358 AC: 1846 AN: 5158

South Asian (SAS) AF: 0.493 AC: 2377 AN: 4820

European-Finnish (FIN) AF: 0.319 AC: 3366 AN: 10562

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.352 AC: 23947 AN: 67968

Other (OTH) AF: 0.395 AC: 834 AN: 2112

Alfa AF: 0.368 Hom.: 1527

Bravo AF: 0.400

Asia WGS AF: 0.435 AC: 1512 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.2
DANN	Benign	0.44
PhyloP100		-0.067

Splicing

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

Other links and lift over

dbSNP: rs328384; hg19: chr16-73839796; COSMIC: COSV107150837;