rs10518048

Variant names:

• chr16-72946841-G-A
• rs10518048
• NM_006885.4:c.3216+3628C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_006885.4(ZFHX3):​c.3216+3628C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0257 in 152,306 control chromosomes in the GnomAD database, including 79 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 0.026 (79 hom., cov: 32)
• Consequence: ZFHX3 NM_006885.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.369
• Publications: 0 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).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0257 (3918/152306) while in subpopulation AFR AF = 0.0364 (1514/41568). AF 95% confidence interval is 0.0349. There are 79 homozygotes in GnomAd4. There are 1867 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 79 AD,AR gene

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.3216+3628C>T		intron	N/A	NP_008816.3
	ZFHX3	NM_001386735.1		c.3216+3628C>T		intron	N/A	NP_001373664.1	Q15911-1
	ZFHX3	NM_001164766.2		c.474+3628C>T		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.3216+3628C>T		intron	N/A	ENSP00000268489.5	Q15911-1
	ZFHX3	ENST00000397992.5	TSL:1	c.474+3628C>T		intron	N/A	ENSP00000438926.3	Q15911-2
	ZFHX3	ENST00000641206.2		c.3216+3628C>T		intron	N/A	ENSP00000493252.1	Q15911-1

Frequencies

GnomAD3 genomes AF: 0.0257 AC: 3915 AN: 152188 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.0363

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.0229

Gnomad ASJ AF: 0.0469

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00932

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0235

Gnomad OTH AF: 0.0383

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

GnomAD4 genome AF: 0.0257 AC: 3918 AN: 152306 Hom.: 79 Cov.: 32 AF XY: 0.0251 AC XY: 1867 AN XY: 74474

African (AFR) AF: 0.0364 AC: 1514 AN: 41568

American (AMR) AF: 0.0229 AC: 350 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0469 AC: 163 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00912 AC: 44 AN: 4826

European-Finnish (FIN) AF: 0.00405 AC: 43 AN: 10622

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0235 AC: 1600 AN: 68042

Other (OTH) AF: 0.0370 AC: 78 AN: 2110

Alfa AF: 0.0239 Hom.: 20

Bravo AF: 0.0285

Asia WGS AF: 0.00924 AC: 33 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.2
DANN	Benign	0.44
PhyloP100		0.37
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10518048; hg19: chr16-72980740;