16-73267403-C-T

Variant names:

• chr16-73267403-C-T
• rs7203768
• NM_001386735.1:c.-710-10267G>A

Variant summary

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

The NM_001386735.1(ZFHX3):​c.-710-10267G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.653 in 151,888 control chromosomes in the GnomAD database, including 32,859 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 0.65 (32859 hom., cov: 30)
• Consequence: ZFHX3 NM_001386735.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.979
• Publications: 2 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 (EAS) allele frequency at 95% confidence interval = 0.799 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFHX3	NM_001386735.1	c.-710-10267G>A		intron_variant	Intron 4 of 16		NP_001373664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFHX3	ENST00000641206.2	c.-1193-10267G>A		intron_variant	Intron 4 of 17			ENSP00000493252.1

Frequencies

GnomAD3 genomes AF: 0.653 AC: 99033 AN: 151770 Hom.: 32823 Cov.: 30

Gnomad AFR AF: 0.754

Gnomad AMI AF: 0.747

Gnomad AMR AF: 0.634

Gnomad ASJ AF: 0.568

Gnomad EAS AF: 0.820

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.608

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.601

Gnomad OTH AF: 0.651

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

GnomAD4 genome AF: 0.653 AC: 99126 AN: 151888 Hom.: 32859 Cov.: 30 AF XY: 0.652 AC XY: 48364 AN XY: 74200

African (AFR) AF: 0.753 AC: 31211 AN: 41426

American (AMR) AF: 0.635 AC: 9678 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.568 AC: 1967 AN: 3466

East Asian (EAS) AF: 0.820 AC: 4223 AN: 5152

South Asian (SAS) AF: 0.535 AC: 2568 AN: 4798

European-Finnish (FIN) AF: 0.608 AC: 6408 AN: 10536

Middle Eastern (MID) AF: 0.524 AC: 153 AN: 292

European-Non Finnish (NFE) AF: 0.601 AC: 40857 AN: 67944

Other (OTH) AF: 0.654 AC: 1381 AN: 2112

Alfa AF: 0.612 Hom.: 15398

Bravo AF: 0.664

Asia WGS AF: 0.679 AC: 2360 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.72
DANN	Benign	0.66
PhyloP100		-0.98

Splicing

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

Other links and lift over

dbSNP: rs7203768; hg19: chr16-73301302;