chr16-73017721-C-T

Variant names:

• chr16-73017721-C-T
• rs2106261
• NM_006885.4:c.-50+30031G>A

Variant summary

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

The NM_006885.4(ZFHX3):​c.-50+30031G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 151,850 control chromosomes in the GnomAD database, including 3,600 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 0.21 (3600 hom., cov: 30)
• Consequence: ZFHX3 NM_006885.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.695
• Publications: 126 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 (EAS) allele frequency at 95% confidence interval = 0.303 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.-50+30031G>A		intron	N/A	NP_008816.3
	ZFHX3	NM_001386735.1		c.-49-57527G>A		intron	N/A	NP_001373664.1	Q15911-1
	ZFHX3	NM_001164766.2		c.-24+40809G>A		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.-50+30031G>A		intron	N/A	ENSP00000268489.5	Q15911-1
	ZFHX3	ENST00000397992.5	TSL:1	c.-24+40809G>A		intron	N/A	ENSP00000438926.3	Q15911-2
	ZFHX3	ENST00000641206.2		c.-50+40809G>A		intron	N/A	ENSP00000493252.1	Q15911-1

Frequencies

GnomAD3 genomes AF: 0.211 AC: 31976 AN: 151732 Hom.: 3596 Cov.: 30

Gnomad AFR AF: 0.259

Gnomad AMI AF: 0.187

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.182

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

GnomAD4 genome AF: 0.211 AC: 31998 AN: 151850 Hom.: 3600 Cov.: 30 AF XY: 0.216 AC XY: 16005 AN XY: 74198

African (AFR) AF: 0.259 AC: 10706 AN: 41360

American (AMR) AF: 0.208 AC: 3182 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 476 AN: 3470

East Asian (EAS) AF: 0.315 AC: 1620 AN: 5138

South Asian (SAS) AF: 0.233 AC: 1114 AN: 4784

European-Finnish (FIN) AF: 0.234 AC: 2474 AN: 10568

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.174 AC: 11841 AN: 67940

Other (OTH) AF: 0.180 AC: 379 AN: 2110

Alfa AF: 0.179 Hom.: 11313

Bravo AF: 0.210

Asia WGS AF: 0.254 AC: 883 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.1
DANN	Benign	0.39
PhyloP100		0.69
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: rs2106261; hg19: chr16-73051620; COSMIC: COSV51738048; COSMIC: COSV51738048;