chr16-73045784-T-C

Variant names:

• chr16-73045784-T-C
• rs7204751
• NM_006885.4:c.-50+1968A>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.-50+1968A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 128,960 control chromosomes in the GnomAD database, including 5,024 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 0.22 (5024 hom., cov: 21)
• Consequence: ZFHX3 NM_006885.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0540
• Publications: 9 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006885.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX3	NM_006885.4	MANE Select	c.-50+1968A>G		intron	N/A	NP_008816.3
	ZFHX3	NM_001386735.1		c.-50+47451A>G		intron	N/A	NP_001373664.1	Q15911-1
	ZFHX3	NM_001164766.2		c.-24+12746A>G		intron	N/A	NP_001158238.1	Q15911-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX3	ENST00000268489.10	TSL:1 MANE Select	c.-50+1968A>G		intron	N/A	ENSP00000268489.5	Q15911-1
	ZFHX3	ENST00000397992.5	TSL:1	c.-24+12746A>G		intron	N/A	ENSP00000438926.3	Q15911-2
	ZFHX3	ENST00000641206.2		c.-50+12746A>G		intron	N/A	ENSP00000493252.1	Q15911-1

Frequencies

GnomAD3 genomes AF: 0.216 AC: 27816 AN: 128922 Hom.: 5018 Cov.: 21

Gnomad AFR AF: 0.492

Gnomad AMI AF: 0.0719

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.0857

Gnomad FIN AF: 0.0793

Gnomad MID AF: 0.156

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.191

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

GnomAD4 genome AF: 0.216 AC: 27834 AN: 128960 Hom.: 5024 Cov.: 21 AF XY: 0.209 AC XY: 12862 AN XY: 61420

African (AFR) AF: 0.491 AC: 16324 AN: 33214

American (AMR) AF: 0.123 AC: 1548 AN: 12628

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 404 AN: 3270

East Asian (EAS) AF: 0.109 AC: 436 AN: 4006

South Asian (SAS) AF: 0.0846 AC: 334 AN: 3948

European-Finnish (FIN) AF: 0.0793 AC: 501 AN: 6320

Middle Eastern (MID) AF: 0.158 AC: 36 AN: 228

European-Non Finnish (NFE) AF: 0.125 AC: 7853 AN: 62728

Other (OTH) AF: 0.190 AC: 337 AN: 1770

Alfa AF: 0.175 Hom.: 8911

Bravo AF: 0.252

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.0
DANN	Benign	0.76
PhyloP100		-0.054
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs7204751; hg19: chr16-73079683;