chr16-73723998-T-G

Variant names:

• chr16-73723998-T-G
• rs2639311
• NM_001386735.1:c.-1124-43758A>C

Variant summary

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

The NM_001386735.1(ZFHX3):​c.-1124-43758A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.874 in 152,198 control chromosomes in the GnomAD database, including 59,048 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 0.87 (59048 hom., cov: 32)
• Consequence: ZFHX3 NM_001386735.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.204
• Publications: 3 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386735.1. 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.-1124-43758A>C		intron	N/A	NP_001373664.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX3	ENST00000641206.2		c.-1607-43758A>C		intron	N/A	ENSP00000493252.1
	ZFHX3	ENST00000641018.1		n.101-43758A>C		intron	N/A
	ZFHX3	ENST00000642085.1		n.103-43758A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.875 AC: 132998 AN: 152080 Hom.: 59020 Cov.: 32

Gnomad AFR AF: 0.717

Gnomad AMI AF: 0.958

Gnomad AMR AF: 0.870

Gnomad ASJ AF: 0.962

Gnomad EAS AF: 0.850

Gnomad SAS AF: 0.881

Gnomad FIN AF: 0.977

Gnomad MID AF: 0.930

Gnomad NFE AF: 0.950

Gnomad OTH AF: 0.892

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

GnomAD4 genome AF: 0.874 AC: 133078 AN: 152198 Hom.: 59048 Cov.: 32 AF XY: 0.874 AC XY: 65068 AN XY: 74410

African (AFR) AF: 0.717 AC: 29762 AN: 41484

American (AMR) AF: 0.870 AC: 13297 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.962 AC: 3341 AN: 3472

East Asian (EAS) AF: 0.850 AC: 4394 AN: 5172

South Asian (SAS) AF: 0.881 AC: 4243 AN: 4818

European-Finnish (FIN) AF: 0.977 AC: 10375 AN: 10616

Middle Eastern (MID) AF: 0.932 AC: 274 AN: 294

European-Non Finnish (NFE) AF: 0.950 AC: 64636 AN: 68032

Other (OTH) AF: 0.891 AC: 1882 AN: 2112

Alfa AF: 0.932 Hom.: 42707

Bravo AF: 0.860

Asia WGS AF: 0.859 AC: 2990 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.7
DANN	Benign	0.50
PhyloP100		-0.20

Splicing

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

Other links and lift over

dbSNP: rs2639311; hg19: chr16-73757897;