NM_006885.4:c.-49-20653G>A

Variant names:

• chr16-72980847-C-T
• rs11640395
• NM_006885.4:c.-49-20653G>A

Variant summary

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

The NM_006885.4(ZFHX3):​c.-49-20653G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 152,022 control chromosomes in the GnomAD database, including 3,366 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 0.21 (3366 hom., cov: 32)
• Consequence: ZFHX3 NM_006885.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.954
• Publications: 4 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.224 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.-49-20653G>A		intron	N/A	NP_008816.3
	ZFHX3	NM_001386735.1		c.-49-20653G>A		intron	N/A	NP_001373664.1
	ZFHX3	NM_001164766.2		c.-23-29882G>A		intron	N/A	NP_001158238.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX3	ENST00000268489.10	TSL:1 MANE Select	c.-49-20653G>A		intron	N/A	ENSP00000268489.5
	ZFHX3	ENST00000397992.5	TSL:1	c.-23-29882G>A		intron	N/A	ENSP00000438926.3
	ZFHX3	ENST00000641206.2		c.-49-20653G>A		intron	N/A	ENSP00000493252.1

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31531 AN: 151904 Hom.: 3355 Cov.: 32

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.0985

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.199

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

GnomAD4 genome AF: 0.208 AC: 31569 AN: 152022 Hom.: 3366 Cov.: 32 AF XY: 0.205 AC XY: 15245 AN XY: 74302

African (AFR) AF: 0.228 AC: 9454 AN: 41452

American (AMR) AF: 0.132 AC: 2015 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 719 AN: 3472

East Asian (EAS) AF: 0.0980 AC: 507 AN: 5176

South Asian (SAS) AF: 0.145 AC: 697 AN: 4808

European-Finnish (FIN) AF: 0.242 AC: 2552 AN: 10540

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.221 AC: 15006 AN: 67982

Other (OTH) AF: 0.195 AC: 412 AN: 2110

Alfa AF: 0.203 Hom.: 5426

Bravo AF: 0.200

Asia WGS AF: 0.118 AC: 413 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.5
DANN	Benign	0.78
PhyloP100		-0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs11640395; hg19: chr16-73014746;