16-72957387-C-T

Variant names:

• chr16-72957387-C-T
• rs2157786
• NM_006885.4:c.2719+40G>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.2719+40G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.659 in 1,552,348 control chromosomes in the GnomAD database, including 343,153 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 0.62 (29617 hom., cov: 31)
  • Exomes 𝑓: 0.66 (313536 hom.)
• Consequence: ZFHX3 NM_006885.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.314
• Publications: 11 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=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.691 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFHX3	NM_006885.4	c.2719+40G>A		intron_variant	Intron 2 of 9	ENST00000268489.10	NP_008816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFHX3	ENST00000268489.10	c.2719+40G>A		intron_variant	Intron 2 of 9	1	NM_006885.4	ENSP00000268489.5
ZFHX3	ENST00000397992.5	c.-23-6422G>A		intron_variant	Intron 1 of 8	1		ENSP00000438926.3
ZFHX3	ENST00000641206.2	c.2719+40G>A		intron_variant	Intron 10 of 17			ENSP00000493252.1

Frequencies

GnomAD3 genomes AF: 0.615 AC: 93516 AN: 151944 Hom.: 29609 Cov.: 31

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.666

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.578

Gnomad EAS AF: 0.447

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.770

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.697

Gnomad OTH AF: 0.615

GnomAD2 exomes AF: 0.616 AC: 126940 AN: 206072 AF XY: 0.621

Gnomad AFR exome AF: 0.485

Gnomad AMR exome AF: 0.508

Gnomad ASJ exome AF: 0.579

Gnomad EAS exome AF: 0.455

Gnomad FIN exome AF: 0.777

Gnomad NFE exome AF: 0.699

Gnomad OTH exome AF: 0.639

GnomAD4 exome AF: 0.664 AC: 929671 AN: 1400288 Hom.: 313536 Cov.: 35 AF XY: 0.660 AC XY: 455040 AN XY: 689064

African (AFR) AF: 0.486 AC: 15477 AN: 31864

American (AMR) AF: 0.515 AC: 19344 AN: 37526

Ashkenazi Jewish (ASJ) AF: 0.577 AC: 12821 AN: 22236

East Asian (EAS) AF: 0.435 AC: 17016 AN: 39102

South Asian (SAS) AF: 0.481 AC: 36175 AN: 75180

European-Finnish (FIN) AF: 0.769 AC: 38405 AN: 49964

Middle Eastern (MID) AF: 0.600 AC: 3271 AN: 5450

European-Non Finnish (NFE) AF: 0.694 AC: 750002 AN: 1081152

Other (OTH) AF: 0.643 AC: 37160 AN: 57814

GnomAD4 genome AF: 0.615 AC: 93576 AN: 152060 Hom.: 29617 Cov.: 31 AF XY: 0.615 AC XY: 45724 AN XY: 74330

African (AFR) AF: 0.496 AC: 20547 AN: 41460

American (AMR) AF: 0.582 AC: 8895 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.578 AC: 2004 AN: 3470

East Asian (EAS) AF: 0.446 AC: 2300 AN: 5156

South Asian (SAS) AF: 0.468 AC: 2256 AN: 4816

European-Finnish (FIN) AF: 0.770 AC: 8150 AN: 10584

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.697 AC: 47347 AN: 67968

Other (OTH) AF: 0.611 AC: 1291 AN: 2114

Alfa AF: 0.660 Hom.: 57884

Bravo AF: 0.595

Asia WGS AF: 0.470 AC: 1637 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.3
DANN	Benign	0.53
PhyloP100		0.31
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: rs2157786; hg19: chr16-72991286; COSMIC: COSV51708980;