rs11075953

Variant names:

• chr16-72965866-A-G
• rs11075953
• NM_006885.4:c.-49-5672T>C

Variant summary

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

The NM_006885.4(ZFHX3):​c.-49-5672T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 152,150 control chromosomes in the GnomAD database, including 8,351 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 0.32 (8351 hom., cov: 32)
• Consequence: ZFHX3 NM_006885.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.669
• 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=-0.78).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFHX3	NM_006885.4	c.-49-5672T>C		intron_variant	Intron 1 of 9	ENST00000268489.10	NP_008816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFHX3	ENST00000268489.10	c.-49-5672T>C		intron_variant	Intron 1 of 9	1	NM_006885.4	ENSP00000268489.5
ZFHX3	ENST00000397992.5	c.-23-14901T>C		intron_variant	Intron 1 of 8	1		ENSP00000438926.3
ZFHX3	ENST00000641206.2	c.-49-5672T>C		intron_variant	Intron 9 of 17			ENSP00000493252.1

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49404 AN: 152034 Hom.: 8342 Cov.: 32

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.335

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.343

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

GnomAD4 genome AF: 0.325 AC: 49442 AN: 152150 Hom.: 8351 Cov.: 32 AF XY: 0.323 AC XY: 24042 AN XY: 74362

African (AFR) AF: 0.274 AC: 11356 AN: 41506

American (AMR) AF: 0.360 AC: 5507 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 1161 AN: 3468

East Asian (EAS) AF: 0.116 AC: 601 AN: 5180

South Asian (SAS) AF: 0.223 AC: 1075 AN: 4824

European-Finnish (FIN) AF: 0.384 AC: 4058 AN: 10562

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.362 AC: 24590 AN: 68006

Other (OTH) AF: 0.339 AC: 715 AN: 2110

Alfa AF: 0.351 Hom.: 11917

Bravo AF: 0.322

Asia WGS AF: 0.157 AC: 548 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.3
DANN	Benign	0.67
PhyloP100		0.67
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: rs11075953; hg19: chr16-72999765;