rs16971384

Variant names:

• chr16-72897186-A-G
• rs16971384
• NM_006885.4:c.3217-7224T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-72897186-A-G
• chr16-72897186-A-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.3217-7224T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.324 in 152,142 control chromosomes in the GnomAD database, including 8,632 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 0.32 (8632 hom., cov: 32)
• Consequence: ZFHX3 NM_006885.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.135
• Publications: 19 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.44 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFHX3	NM_006885.4	c.3217-7224T>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.3217-7224T>C		intron_variant	Intron 3 of 9	1	NM_006885.4	ENSP00000268489.5
ZFHX3	ENST00000397992.5	c.475-7224T>C		intron_variant	Intron 2 of 8	1		ENSP00000438926.3
ZFHX3	ENST00000641206.2	c.3217-7224T>C		intron_variant	Intron 11 of 17			ENSP00000493252.1

Frequencies

GnomAD3 genomes AF: 0.324 AC: 49319 AN: 152024 Hom.: 8614 Cov.: 32

Gnomad AFR AF: 0.445

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.275

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.388

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.308

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

GnomAD4 genome AF: 0.324 AC: 49370 AN: 152142 Hom.: 8632 Cov.: 32 AF XY: 0.325 AC XY: 24144 AN XY: 74386

African (AFR) AF: 0.445 AC: 18463 AN: 41478

American (AMR) AF: 0.275 AC: 4203 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 649 AN: 3468

East Asian (EAS) AF: 0.389 AC: 2004 AN: 5158

South Asian (SAS) AF: 0.369 AC: 1779 AN: 4820

European-Finnish (FIN) AF: 0.249 AC: 2643 AN: 10606

Middle Eastern (MID) AF: 0.284 AC: 83 AN: 292

European-Non Finnish (NFE) AF: 0.274 AC: 18607 AN: 68002

Other (OTH) AF: 0.306 AC: 645 AN: 2106

Alfa AF: 0.290 Hom.: 21591

Bravo AF: 0.330

Asia WGS AF: 0.380 AC: 1319 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.80
DANN	Benign	0.40
PhyloP100		-0.14
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: rs16971384; hg19: chr16-72931085;