rs8056528

Variant names:

• chr16-73002734-T-C
• rs8056528
• NM_006885.4:c.-49-42540A>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.-49-42540A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.298 in 152,122 control chromosomes in the GnomAD database, including 6,835 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 0.30 (6835 hom., cov: 32)
• Consequence: ZFHX3 NM_006885.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.51
• Publications: 5 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=-0.79).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFHX3	NM_006885.4	c.-49-42540A>G		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.-49-42540A>G		intron_variant	Intron 1 of 9	1	NM_006885.4	ENSP00000268489.5
ZFHX3	ENST00000397992.5	c.-23-51769A>G		intron_variant	Intron 1 of 8	1		ENSP00000438926.3
ZFHX3	ENST00000641206.2	c.-49-42540A>G		intron_variant	Intron 9 of 17			ENSP00000493252.1

Frequencies

GnomAD3 genomes AF: 0.297 AC: 45208 AN: 152004 Hom.: 6819 Cov.: 32

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.352

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.288

Gnomad OTH AF: 0.346

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

GnomAD4 genome AF: 0.298 AC: 45258 AN: 152122 Hom.: 6835 Cov.: 32 AF XY: 0.294 AC XY: 21847 AN XY: 74358

African (AFR) AF: 0.318 AC: 13195 AN: 41492

American (AMR) AF: 0.380 AC: 5812 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 1210 AN: 3468

East Asian (EAS) AF: 0.150 AC: 774 AN: 5176

South Asian (SAS) AF: 0.207 AC: 998 AN: 4818

European-Finnish (FIN) AF: 0.238 AC: 2520 AN: 10592

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.288 AC: 19599 AN: 67982

Other (OTH) AF: 0.341 AC: 720 AN: 2110

Alfa AF: 0.296 Hom.: 10075

Bravo AF: 0.315

Asia WGS AF: 0.184 AC: 637 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	11
DANN	Benign	0.66
PhyloP100		1.5
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: rs8056528; hg19: chr16-73036633;