16-73051387-A-G

Variant names:

• chr16-73051387-A-G
• rs8049936
• ENST00000397992.5:c.-24+7143T>C

Variant summary

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

The ENST00000397992.5(ZFHX3):​c.-24+7143T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 152,006 control chromosomes in the GnomAD database, including 9,769 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 0.33 (9769 hom., cov: 32)
• Consequence: ZFHX3 ENST00000397992.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.708
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.547 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000397992.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX3	NM_001386735.1		c.-50+41848T>C		intron	N/A	NP_001373664.1
	ZFHX3	NM_001164766.2		c.-24+7143T>C		intron	N/A	NP_001158238.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX3	ENST00000397992.5	TSL:1	c.-24+7143T>C		intron	N/A	ENSP00000438926.3
	ZFHX3	ENST00000641206.2		c.-50+7143T>C		intron	N/A	ENSP00000493252.1

Frequencies

GnomAD3 genomes AF: 0.328 AC: 49879 AN: 151884 Hom.: 9749 Cov.: 32

Gnomad AFR AF: 0.553

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.260

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.347

Gnomad SAS AF: 0.307

Gnomad FIN AF: 0.209

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.338

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

GnomAD4 genome AF: 0.329 AC: 49953 AN: 152006 Hom.: 9769 Cov.: 32 AF XY: 0.324 AC XY: 24116 AN XY: 74322

African (AFR) AF: 0.553 AC: 22928 AN: 41428

American (AMR) AF: 0.260 AC: 3965 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1065 AN: 3470

East Asian (EAS) AF: 0.348 AC: 1789 AN: 5142

South Asian (SAS) AF: 0.306 AC: 1473 AN: 4814

European-Finnish (FIN) AF: 0.209 AC: 2209 AN: 10590

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15613 AN: 67968

Other (OTH) AF: 0.336 AC: 709 AN: 2112

Alfa AF: 0.256 Hom.: 6854

Bravo AF: 0.341

Asia WGS AF: 0.349 AC: 1212 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	8.9
DANN	Benign	0.33
PhyloP100		0.71
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs8049936; hg19: chr16-73085286;