rs17681554

Variant names:

• chr16-72982869-A-C
• rs17681554
• NM_006885.4:c.-49-22675T>G

Your query was ambiguous. Multiple possible variants found:

• chr16-72982869-A-C
• chr16-72982869-A-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.-49-22675T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.392 in 152,000 control chromosomes in the GnomAD database, including 11,959 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 0.39 (11959 hom., cov: 32)
• Consequence: ZFHX3 NM_006885.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.701
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.414 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX3	NM_006885.4	MANE Select	c.-49-22675T>G		intron	N/A	NP_008816.3
	ZFHX3	NM_001386735.1		c.-49-22675T>G		intron	N/A	NP_001373664.1
	ZFHX3	NM_001164766.2		c.-23-31904T>G		intron	N/A	NP_001158238.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX3	ENST00000268489.10	TSL:1 MANE Select	c.-49-22675T>G		intron	N/A	ENSP00000268489.5
	ZFHX3	ENST00000397992.5	TSL:1	c.-23-31904T>G		intron	N/A	ENSP00000438926.3
	ZFHX3	ENST00000641206.2		c.-49-22675T>G		intron	N/A	ENSP00000493252.1

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59493 AN: 151882 Hom.: 11949 Cov.: 32

Gnomad AFR AF: 0.357

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.437

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.418

Gnomad OTH AF: 0.412

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

GnomAD4 genome AF: 0.392 AC: 59539 AN: 152000 Hom.: 11959 Cov.: 32 AF XY: 0.391 AC XY: 29039 AN XY: 74318

African (AFR) AF: 0.357 AC: 14806 AN: 41446

American (AMR) AF: 0.418 AC: 6389 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.411 AC: 1427 AN: 3468

East Asian (EAS) AF: 0.200 AC: 1032 AN: 5162

South Asian (SAS) AF: 0.322 AC: 1550 AN: 4814

European-Finnish (FIN) AF: 0.437 AC: 4618 AN: 10576

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.418 AC: 28430 AN: 67942

Other (OTH) AF: 0.407 AC: 859 AN: 2112

Alfa AF: 0.406 Hom.: 37078

Bravo AF: 0.391

Asia WGS AF: 0.253 AC: 882 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.0
DANN	Benign	0.57
PhyloP100		0.70
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: rs17681554; hg19: chr16-73016768;