16-72963848-G-T

Variant names:

• chr16-72963848-G-T
• rs4788683
• NM_006885.4:c.-49-3654C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_006885.4(ZFHX3):​c.-49-3654C>A variant causes a intron change. The variant allele was found at a frequency of 0.382 in 151,952 control chromosomes in the GnomAD database, including 11,402 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 0.38 (11402 hom., cov: 32)
• Consequence: ZFHX3 NM_006885.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.54
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.421 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFHX3	NM_006885.4	c.-49-3654C>A		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.-49-3654C>A		intron_variant	Intron 1 of 9	1	NM_006885.4	ENSP00000268489.5
ZFHX3	ENST00000397992.5	c.-23-12883C>A		intron_variant	Intron 1 of 8	1		ENSP00000438926.3
ZFHX3	ENST00000641206.2	c.-49-3654C>A		intron_variant	Intron 9 of 17			ENSP00000493252.1

Frequencies

GnomAD3 genomes AF: 0.382 AC: 57973 AN: 151832 Hom.: 11377 Cov.: 32

Gnomad AFR AF: 0.426

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.404

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.392

Gnomad OTH AF: 0.343

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

GnomAD4 genome AF: 0.382 AC: 58041 AN: 151952 Hom.: 11402 Cov.: 32 AF XY: 0.379 AC XY: 28150 AN XY: 74256

African (AFR) AF: 0.427 AC: 17666 AN: 41396

American (AMR) AF: 0.272 AC: 4154 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1148 AN: 3468

East Asian (EAS) AF: 0.157 AC: 810 AN: 5170

South Asian (SAS) AF: 0.403 AC: 1941 AN: 4816

European-Finnish (FIN) AF: 0.432 AC: 4559 AN: 10558

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.392 AC: 26631 AN: 67956

Other (OTH) AF: 0.349 AC: 737 AN: 2112

Alfa AF: 0.377 Hom.: 18530

Bravo AF: 0.366

Asia WGS AF: 0.319 AC: 1111 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	15
DANN	Benign	0.82
PhyloP100		4.5
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: rs4788683; hg19: chr16-72997747;