16-72947041-C-T

Variant names:

• chr16-72947041-C-T
• rs17680796
• NM_006885.4:c.3216+3428G>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.3216+3428G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 152,086 control chromosomes in the GnomAD database, including 7,811 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 0.29 (7811 hom., cov: 32)
• Consequence: ZFHX3 NM_006885.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.06
• Publications: 7 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=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.377 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.3216+3428G>A		intron	N/A	NP_008816.3
	ZFHX3	NM_001386735.1		c.3216+3428G>A		intron	N/A	NP_001373664.1
	ZFHX3	NM_001164766.2		c.474+3428G>A		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.3216+3428G>A		intron	N/A	ENSP00000268489.5
	ZFHX3	ENST00000397992.5	TSL:1	c.474+3428G>A		intron	N/A	ENSP00000438926.3
	ZFHX3	ENST00000641206.2		c.3216+3428G>A		intron	N/A	ENSP00000493252.1

Frequencies

GnomAD3 genomes AF: 0.290 AC: 44067 AN: 151968 Hom.: 7807 Cov.: 32

Gnomad AFR AF: 0.0782

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.345

Gnomad EAS AF: 0.320

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.311

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

GnomAD4 genome AF: 0.290 AC: 44080 AN: 152086 Hom.: 7811 Cov.: 32 AF XY: 0.294 AC XY: 21888 AN XY: 74336

African (AFR) AF: 0.0781 AC: 3240 AN: 41508

American (AMR) AF: 0.339 AC: 5173 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 1197 AN: 3466

East Asian (EAS) AF: 0.320 AC: 1654 AN: 5174

South Asian (SAS) AF: 0.251 AC: 1212 AN: 4820

European-Finnish (FIN) AF: 0.432 AC: 4562 AN: 10570

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.381 AC: 25914 AN: 67958

Other (OTH) AF: 0.311 AC: 656 AN: 2112

Alfa AF: 0.341 Hom.: 26263

Bravo AF: 0.274

Asia WGS AF: 0.278 AC: 970 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.16
DANN	Benign	0.69
PhyloP100		-4.1
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: rs17680796; hg19: chr16-72980940;