rs12596992

Variant names:

• chr16-72945144-C-G
• rs12596992
• NM_006885.4:c.3216+5325G>C

Your query was ambiguous. Multiple possible variants found:

• chr16-72945144-C-G
• chr16-72945144-C-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.3216+5325G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 151,864 control chromosomes in the GnomAD database, including 3,724 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 0.18 (3724 hom., cov: 32)
• Consequence: ZFHX3 NM_006885.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.850
• Publications: 4 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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFHX3	NM_006885.4	c.3216+5325G>C		intron_variant	Intron 3 of 9	ENST00000268489.10	NP_008816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFHX3	ENST00000268489.10	c.3216+5325G>C		intron_variant	Intron 3 of 9	1	NM_006885.4	ENSP00000268489.5
ZFHX3	ENST00000397992.5	c.474+5325G>C		intron_variant	Intron 2 of 8	1		ENSP00000438926.3
ZFHX3	ENST00000641206.2	c.3216+5325G>C		intron_variant	Intron 11 of 17			ENSP00000493252.1

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27744 AN: 151746 Hom.: 3722 Cov.: 32

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.596

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0914

Gnomad OTH AF: 0.158

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

GnomAD4 genome AF: 0.183 AC: 27779 AN: 151864 Hom.: 3724 Cov.: 32 AF XY: 0.191 AC XY: 14182 AN XY: 74190

African (AFR) AF: 0.307 AC: 12695 AN: 41362

American (AMR) AF: 0.127 AC: 1944 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 417 AN: 3470

East Asian (EAS) AF: 0.595 AC: 3068 AN: 5160

South Asian (SAS) AF: 0.261 AC: 1252 AN: 4794

European-Finnish (FIN) AF: 0.169 AC: 1780 AN: 10530

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.0914 AC: 6210 AN: 67966

Other (OTH) AF: 0.156 AC: 328 AN: 2106

Alfa AF: 0.0527 Hom.: 65

Bravo AF: 0.184

Asia WGS AF: 0.412 AC: 1428 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.21
DANN	Benign	0.25
PhyloP100		-0.85
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: rs12596992; hg19: chr16-72979043;