rs1877354

Variant names:

• chr16-73851250-A-C
• rs1877354
• NM_001386735.1:c.-1125+40401T>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+40401T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.333 in 151,930 control chromosomes in the GnomAD database, including 10,275 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 (10275 hom., cov: 32)
• Consequence: ZFHX3 NM_001386735.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.151
• Publications: 6 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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386735.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX3	NM_001386735.1		c.-1125+40401T>G		intron	N/A	NP_001373664.1	Q15911-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX3	ENST00000641206.2		c.-1608+40401T>G		intron	N/A	ENSP00000493252.1	Q15911-1
	ZFHX3	ENST00000641018.1		n.100+40401T>G		intron	N/A
	ZFHX3	ENST00000642085.1		n.102+40401T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50635 AN: 151812 Hom.: 10275 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.321

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.434

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.449

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.461

Gnomad OTH AF: 0.331

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

GnomAD4 genome AF: 0.333 AC: 50637 AN: 151930 Hom.: 10275 Cov.: 32 AF XY: 0.329 AC XY: 24433 AN XY: 74224

African (AFR) AF: 0.121 AC: 5014 AN: 41450

American (AMR) AF: 0.280 AC: 4281 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.434 AC: 1503 AN: 3466

East Asian (EAS) AF: 0.140 AC: 720 AN: 5156

South Asian (SAS) AF: 0.413 AC: 1977 AN: 4788

European-Finnish (FIN) AF: 0.449 AC: 4734 AN: 10538

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.461 AC: 31305 AN: 67948

Other (OTH) AF: 0.331 AC: 698 AN: 2110

Alfa AF: 0.414 Hom.: 23420

Bravo AF: 0.304

Asia WGS AF: 0.263 AC: 916 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.7
DANN	Benign	0.64
PhyloP100		0.15

Splicing

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

Other links and lift over

dbSNP: rs1877354; hg19: chr16-73885149;