16-72995261-T-C

Variant names:

• chr16-72995261-T-C
• rs7193343
• NM_006885.4:c.-49-35067A>G

Variant summary

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

The NM_006885.4(ZFHX3):​c.-49-35067A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.78 in 152,012 control chromosomes in the GnomAD database, including 46,978 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 0.78 (46978 hom., cov: 31)
• Consequence: ZFHX3 NM_006885.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.484
• Publications: 99 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.824 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX3	NM_006885.4	MANE Select	c.-49-35067A>G		intron	N/A	NP_008816.3
	ZFHX3	NM_001386735.1		c.-49-35067A>G		intron	N/A	NP_001373664.1	Q15911-1
	ZFHX3	NM_001164766.2		c.-23-44296A>G		intron	N/A	NP_001158238.1	Q15911-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX3	ENST00000268489.10	TSL:1 MANE Select	c.-49-35067A>G		intron	N/A	ENSP00000268489.5	Q15911-1
	ZFHX3	ENST00000397992.5	TSL:1	c.-23-44296A>G		intron	N/A	ENSP00000438926.3	Q15911-2
	ZFHX3	ENST00000641206.2		c.-49-35067A>G		intron	N/A	ENSP00000493252.1	Q15911-1

Frequencies

GnomAD3 genomes AF: 0.780 AC: 118515 AN: 151896 Hom.: 46944 Cov.: 31

Gnomad AFR AF: 0.762

Gnomad AMI AF: 0.815

Gnomad AMR AF: 0.779

Gnomad ASJ AF: 0.861

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.676

Gnomad FIN AF: 0.748

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.830

Gnomad OTH AF: 0.809

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

GnomAD4 genome AF: 0.780 AC: 118603 AN: 152012 Hom.: 46978 Cov.: 31 AF XY: 0.770 AC XY: 57203 AN XY: 74264

African (AFR) AF: 0.762 AC: 31591 AN: 41460

American (AMR) AF: 0.778 AC: 11889 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.861 AC: 2986 AN: 3470

East Asian (EAS) AF: 0.361 AC: 1862 AN: 5154

South Asian (SAS) AF: 0.676 AC: 3243 AN: 4800

European-Finnish (FIN) AF: 0.748 AC: 7899 AN: 10558

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.830 AC: 56428 AN: 67984

Other (OTH) AF: 0.810 AC: 1706 AN: 2106

Alfa AF: 0.814 Hom.: 244911

Bravo AF: 0.782

Asia WGS AF: 0.570 AC: 1982 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.31
DANN	Benign	0.71
PhyloP100		-0.48
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: rs7193343; hg19: chr16-73029160;