rs13336412

Variant names:

• chr16-72948050-C-A
• rs13336412
• NM_006885.4:c.3216+2419G>T

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+2419G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.583 in 152,030 control chromosomes in the GnomAD database, including 26,657 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 0.58 (26657 hom., cov: 32)
• Consequence: ZFHX3 NM_006885.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.76
• Publications: 12 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.703 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFHX3	NM_006885.4	c.3216+2419G>T		intron_variant	Intron 3 of 9	ENST00000268489.10	NP_008816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFHX3	ENST00000268489.10	c.3216+2419G>T		intron_variant	Intron 3 of 9	1	NM_006885.4	ENSP00000268489.5
ZFHX3	ENST00000397992.5	c.474+2419G>T		intron_variant	Intron 2 of 8	1		ENSP00000438926.3
ZFHX3	ENST00000641206.2	c.3216+2419G>T		intron_variant	Intron 11 of 17			ENSP00000493252.1

Frequencies

GnomAD3 genomes AF: 0.583 AC: 88609 AN: 151912 Hom.: 26638 Cov.: 32

Gnomad AFR AF: 0.431

Gnomad AMI AF: 0.668

Gnomad AMR AF: 0.714

Gnomad ASJ AF: 0.631

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.605

Gnomad FIN AF: 0.622

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.642

Gnomad OTH AF: 0.613

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

GnomAD4 genome AF: 0.583 AC: 88654 AN: 152030 Hom.: 26657 Cov.: 32 AF XY: 0.586 AC XY: 43521 AN XY: 74308

African (AFR) AF: 0.431 AC: 17867 AN: 41480

American (AMR) AF: 0.714 AC: 10910 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.631 AC: 2190 AN: 3472

East Asian (EAS) AF: 0.475 AC: 2439 AN: 5138

South Asian (SAS) AF: 0.606 AC: 2915 AN: 4812

European-Finnish (FIN) AF: 0.622 AC: 6578 AN: 10574

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.642 AC: 43663 AN: 67972

Other (OTH) AF: 0.615 AC: 1295 AN: 2106

Alfa AF: 0.618 Hom.: 14554

Bravo AF: 0.585

Asia WGS AF: 0.542 AC: 1886 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.035
DANN	Benign	0.58
PhyloP100		-1.8
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: rs13336412; hg19: chr16-72981949;