chr16-72969820-T-C

Variant names:

• chr16-72969820-T-C
• rs9937546
• NM_006885.4:c.-49-9626A>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.-49-9626A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 152,088 control chromosomes in the GnomAD database, including 8,751 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 0.33 (8751 hom., cov: 32)
• Consequence: ZFHX3 NM_006885.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0160
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.401 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.-49-9626A>G		intron	N/A	NP_008816.3
	ZFHX3	NM_001386735.1		c.-49-9626A>G		intron	N/A	NP_001373664.1
	ZFHX3	NM_001164766.2		c.-23-18855A>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.-49-9626A>G		intron	N/A	ENSP00000268489.5
	ZFHX3	ENST00000397992.5	TSL:1	c.-23-18855A>G		intron	N/A	ENSP00000438926.3
	ZFHX3	ENST00000641206.2		c.-49-9626A>G		intron	N/A	ENSP00000493252.1

Frequencies

GnomAD3 genomes AF: 0.328 AC: 49910 AN: 151970 Hom.: 8728 Cov.: 32

Gnomad AFR AF: 0.405

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.0600

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.374

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.293

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

GnomAD4 genome AF: 0.329 AC: 49973 AN: 152088 Hom.: 8751 Cov.: 32 AF XY: 0.323 AC XY: 24024 AN XY: 74352

African (AFR) AF: 0.406 AC: 16824 AN: 41464

American (AMR) AF: 0.194 AC: 2967 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 920 AN: 3468

East Asian (EAS) AF: 0.0602 AC: 311 AN: 5170

South Asian (SAS) AF: 0.186 AC: 897 AN: 4818

European-Finnish (FIN) AF: 0.374 AC: 3965 AN: 10592

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.341 AC: 23154 AN: 67974

Other (OTH) AF: 0.290 AC: 614 AN: 2114

Alfa AF: 0.319 Hom.: 11878

Bravo AF: 0.317

Asia WGS AF: 0.139 AC: 488 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	1.2
DANN	Benign	0.53
PhyloP100		-0.016
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: rs9937546; hg19: chr16-73003719;