rs719353

Variant names:

• chr16-73008652-G-A
• rs719353
• NM_006885.4:c.-50+39100C>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.-50+39100C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.572 in 151,924 control chromosomes in the GnomAD database, including 26,553 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 0.57 (26553 hom., cov: 31)
• Consequence: ZFHX3 NM_006885.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.15
• 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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.821 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFHX3	NM_006885.4	c.-50+39100C>T		intron_variant	Intron 1 of 9	ENST00000268489.10	NP_008816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFHX3	ENST00000268489.10	c.-50+39100C>T		intron_variant	Intron 1 of 9	1	NM_006885.4	ENSP00000268489.5
ZFHX3	ENST00000397992.5	c.-24+49878C>T		intron_variant	Intron 1 of 8	1		ENSP00000438926.3
ZFHX3	ENST00000641206.2	c.-49-48458C>T		intron_variant	Intron 9 of 17			ENSP00000493252.1

Frequencies

GnomAD3 genomes AF: 0.571 AC: 86739 AN: 151808 Hom.: 26506 Cov.: 31

Gnomad AFR AF: 0.774

Gnomad AMI AF: 0.536

Gnomad AMR AF: 0.616

Gnomad ASJ AF: 0.432

Gnomad EAS AF: 0.841

Gnomad SAS AF: 0.548

Gnomad FIN AF: 0.490

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.440

Gnomad OTH AF: 0.559

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

GnomAD4 genome AF: 0.572 AC: 86839 AN: 151924 Hom.: 26553 Cov.: 31 AF XY: 0.577 AC XY: 42826 AN XY: 74270

African (AFR) AF: 0.774 AC: 32098 AN: 41454

American (AMR) AF: 0.616 AC: 9393 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.432 AC: 1498 AN: 3466

East Asian (EAS) AF: 0.842 AC: 4353 AN: 5172

South Asian (SAS) AF: 0.548 AC: 2639 AN: 4812

European-Finnish (FIN) AF: 0.490 AC: 5165 AN: 10538

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.440 AC: 29897 AN: 67930

Other (OTH) AF: 0.555 AC: 1171 AN: 2110

Alfa AF: 0.485 Hom.: 77008

Bravo AF: 0.595

Asia WGS AF: 0.679 AC: 2359 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	9.7
DANN	Benign	0.28
PhyloP100		1.1
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: rs719353; hg19: chr16-73042551;