16-73817443-T-C

Variant names:

• chr16-73817443-T-C
• rs328345
• NM_001386735.1:c.-1125+74208A>G

Variant summary

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

The NM_001386735.1(ZFHX3):​c.-1125+74208A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.434 in 152,094 control chromosomes in the GnomAD database, including 14,770 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 0.43 (14770 hom., cov: 32)
• Consequence: ZFHX3 NM_001386735.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.466
• Publications: 5 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=-0.52).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.547 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFHX3	NM_001386735.1	c.-1125+74208A>G		intron_variant	Intron 1 of 16		NP_001373664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFHX3	ENST00000641206.2	c.-1608+74208A>G		intron_variant	Intron 1 of 17			ENSP00000493252.1
ZFHX3	ENST00000641018.1	n.100+74208A>G		intron_variant	Intron 1 of 1
ZFHX3	ENST00000642085.1	n.102+74208A>G		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.434 AC: 65942 AN: 151976 Hom.: 14738 Cov.: 32

Gnomad AFR AF: 0.552

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.378

Gnomad ASJ AF: 0.276

Gnomad EAS AF: 0.303

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.388

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

GnomAD4 genome AF: 0.434 AC: 66029 AN: 152094 Hom.: 14770 Cov.: 32 AF XY: 0.430 AC XY: 31972 AN XY: 74360

African (AFR) AF: 0.553 AC: 22922 AN: 41464

American (AMR) AF: 0.378 AC: 5784 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 956 AN: 3470

East Asian (EAS) AF: 0.303 AC: 1561 AN: 5158

South Asian (SAS) AF: 0.306 AC: 1477 AN: 4826

European-Finnish (FIN) AF: 0.412 AC: 4363 AN: 10582

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.409 AC: 27778 AN: 67982

Other (OTH) AF: 0.390 AC: 825 AN: 2116

Alfa AF: 0.395 Hom.: 20267

Bravo AF: 0.431

Asia WGS AF: 0.335 AC: 1167 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	7.2
DANN	Benign	0.49
PhyloP100		0.47

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs328345; hg19: chr16-73851342;