16-72958864-T-G

Variant names:

• chr16-72958864-T-G
• rs16971436
• NM_006885.4:c.1282A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_006885.4(ZFHX3):​c.1282A>C​(p.Thr428Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0306 in 1,613,332 control chromosomes in the GnomAD database, including 3,457 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T428I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.063 (673 hom., cov: 33)
  • Exomes 𝑓: 0.027 (2784 hom.)
• Consequence: ZFHX3 NM_006885.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 4.37
• Publications: 16 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014021397).
• BP6: Variant 16-72958864-T-G is Benign according to our data. Variant chr16-72958864-T-G is described in ClinVar as Benign. ClinVar VariationId is 3059393.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.176 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX3	NM_006885.4	MANE Select	c.1282A>C	p.Thr428Pro	missense	Exon 2 of 10	NP_008816.3
	ZFHX3	NM_001386735.1		c.1282A>C	p.Thr428Pro	missense	Exon 9 of 17	NP_001373664.1
	ZFHX3	NM_001164766.2		c.-23-7899A>C		intron	N/A	NP_001158238.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFHX3	ENST00000268489.10	TSL:1 MANE Select	c.1282A>C	p.Thr428Pro	missense	Exon 2 of 10	ENSP00000268489.5
	ZFHX3	ENST00000397992.5	TSL:1	c.-23-7899A>C		intron	N/A	ENSP00000438926.3
	ZFHX3	ENST00000641206.2		c.1282A>C	p.Thr428Pro	missense	Exon 10 of 18	ENSP00000493252.1

Frequencies

GnomAD3 genomes AF: 0.0626 AC: 9519 AN: 152010 Hom.: 665 Cov.: 33

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.0198

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.0826

Gnomad SAS AF: 0.0330

Gnomad FIN AF: 0.0656

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.0585

GnomAD2 exomes AF: 0.0714 AC: 17776 AN: 248982 AF XY: 0.0601

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.302

Gnomad ASJ exome AF: 0.0121

Gnomad EAS exome AF: 0.0841

Gnomad FIN exome AF: 0.0603

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.0566

GnomAD4 exome AF: 0.0273 AC: 39868 AN: 1461206 Hom.: 2784 Cov.: 87 AF XY: 0.0261 AC XY: 18935 AN XY: 726796

African (AFR) AF: 0.111 AC: 3709 AN: 33476

American (AMR) AF: 0.290 AC: 12959 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 288 AN: 26094

East Asian (EAS) AF: 0.0832 AC: 3300 AN: 39686

South Asian (SAS) AF: 0.0334 AC: 2877 AN: 86156

European-Finnish (FIN) AF: 0.0566 AC: 3023 AN: 53384

Middle Eastern (MID) AF: 0.0198 AC: 114 AN: 5760

European-Non Finnish (NFE) AF: 0.0104 AC: 11572 AN: 1111604

Other (OTH) AF: 0.0336 AC: 2026 AN: 60352

GnomAD4 genome AF: 0.0628 AC: 9548 AN: 152126 Hom.: 673 Cov.: 33 AF XY: 0.0671 AC XY: 4990 AN XY: 74378

African (AFR) AF: 0.109 AC: 4515 AN: 41496

American (AMR) AF: 0.182 AC: 2776 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3470

East Asian (EAS) AF: 0.0822 AC: 423 AN: 5144

South Asian (SAS) AF: 0.0328 AC: 158 AN: 4818

European-Finnish (FIN) AF: 0.0656 AC: 695 AN: 10592

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0116 AC: 789 AN: 68014

Other (OTH) AF: 0.0593 AC: 125 AN: 2108

Alfa AF: 0.0259 Hom.: 331

Bravo AF: 0.0760

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.102 AC: 450

ESP6500EA AF: 0.0118 AC: 101

ExAC AF: 0.0614 AC: 7452

EpiCase AF: 0.0122

EpiControl AF: 0.0128

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	ZFHX3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.076
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PhyloP100		4.4
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.15
Sift	Benign	0.10	T
Sift4G	Benign	0.13	T
Polyphen		0.017	B
Vest4		0.077
MPC		0.54
ClinPred		0.0098	T
GERP RS		4.9
Varity_R		0.30
gMVP		0.066
Mutation Taster		=51/49	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: rs16971436; hg19: chr16-72992763; COSMIC: COSV51707630;