NM_006885.4:c.3217-5067T>G

Variant names:

• chr16-72895029-A-C
• rs2157787
• NM_006885.4:c.3217-5067T>G

Variant summary

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

The NM_006885.4(ZFHX3):​c.3217-5067T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.451 in 152,190 control chromosomes in the GnomAD database, including 18,110 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 0.45 (18110 hom., cov: 33)
• Consequence: ZFHX3 NM_006885.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.656
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.733 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFHX3	NM_006885.4	c.3217-5067T>G		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.3217-5067T>G		intron_variant	Intron 3 of 9	1	NM_006885.4	ENSP00000268489.5
ZFHX3	ENST00000397992.5	c.475-5067T>G		intron_variant	Intron 2 of 8	1		ENSP00000438926.3
ZFHX3	ENST00000641206.2	c.3217-5067T>G		intron_variant	Intron 11 of 17			ENSP00000493252.1

Frequencies

GnomAD3 genomes AF: 0.451 AC: 68595 AN: 152070 Hom.: 18061 Cov.: 33

Gnomad AFR AF: 0.739

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.411

Gnomad SAS AF: 0.420

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.338

Gnomad OTH AF: 0.415

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

GnomAD4 genome AF: 0.451 AC: 68690 AN: 152190 Hom.: 18110 Cov.: 33 AF XY: 0.447 AC XY: 33235 AN XY: 74400

African (AFR) AF: 0.740 AC: 30720 AN: 41524

American (AMR) AF: 0.344 AC: 5256 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 882 AN: 3466

East Asian (EAS) AF: 0.412 AC: 2130 AN: 5168

South Asian (SAS) AF: 0.419 AC: 2020 AN: 4824

European-Finnish (FIN) AF: 0.313 AC: 3321 AN: 10598

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.338 AC: 22961 AN: 67996

Other (OTH) AF: 0.418 AC: 884 AN: 2114

Alfa AF: 0.368 Hom.: 17763

Bravo AF: 0.466

Asia WGS AF: 0.442 AC: 1533 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.8
DANN	Benign	0.38
PhyloP100		-0.66
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: rs2157787; hg19: chr16-72928928;