chr16-72988374-G-A

Variant names:

• chr16-72988374-G-A
• rs17692597
• NM_006885.4:c.-49-28180C>T

Variant summary

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

The NM_006885.4(ZFHX3):​c.-49-28180C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 152,076 control chromosomes in the GnomAD database, including 5,641 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 0.26 (5641 hom., cov: 32)
• Consequence: ZFHX3 NM_006885.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0620
• Publications: 1 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.326 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.-49-28180C>T		intron	N/A	NP_008816.3
	ZFHX3	NM_001386735.1		c.-49-28180C>T		intron	N/A	NP_001373664.1
	ZFHX3	NM_001164766.2		c.-23-37409C>T		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.-49-28180C>T		intron	N/A	ENSP00000268489.5
	ZFHX3	ENST00000397992.5	TSL:1	c.-23-37409C>T		intron	N/A	ENSP00000438926.3
	ZFHX3	ENST00000641206.2		c.-49-28180C>T		intron	N/A	ENSP00000493252.1

Frequencies

GnomAD3 genomes AF: 0.263 AC: 39923 AN: 151958 Hom.: 5633 Cov.: 32

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.0990

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.285

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

GnomAD4 genome AF: 0.263 AC: 39953 AN: 152076 Hom.: 5641 Cov.: 32 AF XY: 0.263 AC XY: 19516 AN XY: 74338

African (AFR) AF: 0.174 AC: 7236 AN: 41490

American (AMR) AF: 0.333 AC: 5096 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 1019 AN: 3468

East Asian (EAS) AF: 0.0995 AC: 515 AN: 5178

South Asian (SAS) AF: 0.198 AC: 953 AN: 4816

European-Finnish (FIN) AF: 0.323 AC: 3413 AN: 10564

Middle Eastern (MID) AF: 0.240 AC: 70 AN: 292

European-Non Finnish (NFE) AF: 0.307 AC: 20852 AN: 67958

Other (OTH) AF: 0.282 AC: 594 AN: 2108

Alfa AF: 0.289 Hom.: 25646

Bravo AF: 0.261

Asia WGS AF: 0.144 AC: 500 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.9
DANN	Benign	0.70
PhyloP100		0.062
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: rs17692597; hg19: chr16-73022273;